Leukemia

Cancer Genetics Causes of Cancer Diagnosis and Treatment of Cancer Leukemia Myeloma Prevention of Cancer Skin Cancer Stages of Cancer Development Testicular Cancer

.Leukemia Donna M.D. Bozzone Ph.

ISBN-13: 978-0-7910-8822-7 (hardcover : alk. p. All rights reserved. recording.chelseahouse. II. paper) ISBN-10: 0-7910-8822-7 (hardcover : alk. All links and Web addresses were checked and verified to be correct at the time of publication. You can find Chelsea House on the World Wide Web at http://www. electronic or mechanical. Please call our Special Sales Department in New York at (212) 967-8800 or (800) 322-8755. some addresses and links may have changed since publication and may no longer be valid. For information.com Text design by James Scotto-Lavino Cover design by Ben Peterson Illustrations by Chris and Elisa Scherer and Melissa Ericksen Printed in the United States of America Bang EJB 10 9 8 7 6 5 4 3 2 1 This book is printed on acid-free paper. Leukemia. Leukemia / Donna M. contact: Chelsea House An imprint of Infobase Publishing 132 West 31st Street New York NY 10001 library of Congress Cataloging-in-Publication Data Bozzone.B69 2009 616. — (Biology of cancer) Includes bibliographical references and index. I. including photocopying. Inc. Bozzone. cm. or by any information storage or retrieval systems. RC643. institutions. or sales promotions. No part of this book may be reproduced or utilized in any form or by any means. Title. associations. paper) 1. Donna M. Because of the dynamic nature of the Web.99’419—dc22 2008050881 Chelsea House books are available at special discounts when purchased in bulk quantities for businesses. . Series.THE Biology of CanCEr: lEukEmia Copyright © 2009 by Infobase Publishing. without permission in writing from the publisher.

Treatment. and Prevention of Leukemia Notes Glossary Bibliography Further Resources Index About the Author 116 135 140 149 160 162 168 .Contents ♦ Foreword 6 11 23 38 54 71 88 1 What Is Leukemia? 2 The History of Cancer and Leukemia 3 Blood Cell Development and Function 4 Leukemias Are Not All the Same 5 Childhood Leukemia 6 External Risk Factors and Causes of Leukemia 7 Internal Responses to Risk Factors: Genes and Chromosome Changes 102 8 Diagnosis.

Foreword
♦

A

pproximately 1,500 people die each day of cancer in the United States. Worldwide, more than 8 million new cases are diagnosed

each year. In affluent, developed nations such as the United States, around 1 out of 3 people will develop cancer in his or her lifetime. As deaths from infection and malnutrition become less prevalent in developing areas of the world, people live longer and cancer incidence increases to become a leading cause of mortality. Clearly, few people are left untouched by this disease, because of either their own illness or that of loved ones. This situation leaves us with many questions: What causes cancer? Can we prevent it? Is there a cure? Cancer did not originate in the modern world. Evidence of humans afflicted with cancer dates from ancient times. Examinations of bones from skeletons that are more than 3,000 years old reveal structures that appear to be tumors. Records from ancient Egypt, written more than 4,000 years ago, describe breast cancers. Possible cases of bone tumors have been observed in Egyptian mummies that are more than 5,000 years old. It is even possible that our species’ ancestors developed cancer. In 1932 Louis Leakey discovered a jawbone from either Australopithecus or Homo erectus, which possessed what appeared to be a tumor. Cancer specialists examined the jawbone and suggested that the tumor was due to Burkitt’s lymphoma, a type of cancer that affects the immune system. 

Foreword It is likely that cancer has been a concern for the human lineage for at least a million years. Human beings have been searching for ways to treat and cure cancer since ancient times, but cancer is becoming an even greater problem today. Because life expectancy increased dramatically in the twentieth century because of public health successes such as improvements in our ability to prevent and fight infectious disease, more people live long enough to develop cancer. Children and young adults can develop cancer, but the chance of developing the disease increases as a person ages. Now that so many people live longer, cancer incidence has increased dramatically in the population. As a consequence, the prevalence of cancer came to the forefront as a public health concern by the middle of the twentieth century. In 1971 President Richard Nixon signed the National Cancer Act and thus declared “war” on cancer. The National Cancer Act brought cancer research to the forefront and provided funding and a mandate to spur research to the National Cancer Institute. During the years since that action, research laboratories have made significant progress toward understanding cancer. Surprisingly, the most dramatic insights came from learning how normal cells function, and by comparing that to what goes wrong in cancer cells. Many people think of cancer as a single disease, but it actually comprises more than 100 different disorders in normal cell and tissue function. Nevertheless, all cancers have one feature in common: All are diseases of uncontrolled cell division. Under normal circumstances, the body regulates the production of new cells very precisely. In cancer cells, particular defects in deoxyribonucleic acid, or DNA, lead to breakdowns in the cell communication and growth control normal in healthy cells. Having escaped these controls, cancer cells can become invasive and spread to other parts of the body. As a 



Leukemia consequence, normal tissue and organ functions may be seriously disrupted. Ultimately cancer can be fatal. Even though cancer is a serious disease, modern research has provided many reasons to feel hopeful about the future of cancer treatment and prevention. First, scientists have learned a great deal about the specific genes involved in cancer. This information paves the way for improved early detection, such as identifying individuals with a genetic predisposition to cancer and monitoring their health to ensure the earliest possible detection. Second, knowledge of both the specific genes involved in cancer and the proteins made by cancer cells has made it possible to develop very specific and effective treatments for certain cancers. For example, childhood leukemia, once almost certainly fatal, now can be treated successfully in the great majority of cases. Similarly, improved understanding of cancer cell proteins led to the development of new anticancer drugs such as Herceptin, which is used to treat certain types of breast tumors. Third, many cancers are preventable. In fact, it is likely that more than 50 percent of cancers would never occur if people avoided smoking, overexposure to sun, a high-fat diet, and a sedentary lifestyle. People have tremendous power to reduce their chances of developing cancer by making good health and lifestyle decisions. Even if treatments become perfect, prevention is still preferable to avoid the anxiety of a diagnosis and the potential pain of treatment. The books in the Biology of Cancer series reveal information about the causes of the disease; the DNA changes that result in tumor formation; ways to prevent, detect, and treat cancer; and detailed accounts of specific types of cancers that occur in particular tissues or organs. Books in this series describe what happens to cells as they lose growth control and how specific cancers affect the body. The Biology of Cancer also provides insights into the studies undertaken, the research experiments

Donna M. Even more. readers get to see beyond “the facts” and understand more about the process of biomedical research. affording scientists the challenge of scientific problem solving as well as the opportunity to engage in work that is likely to directly benefit people’s health and well-being. I look forward to your joining the community of scientists. Professor of Biology Saint Michael’s College Colchester. Ph. Perhaps some of your questions will inspire you to follow your own path of discovery. and the scientists involved in the development of the present state of knowledge of this disease. Vermont  . Bozzone. after all. I hope that the books in this series will help readers learn about cancer.Foreword done. Finally. Cancer research is at a very exciting crossroads. the books in the Biology of Cancer series provide information to help readers make healthy choices that can reduce the risk of cancer. there is still a lot of work to be done. If so. I hope that these books will capture your interest and awaken your curiosity about cancer so that you ask questions for which scientists presently have no answers. In this way.D.

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Neil Keller was a 31-year-old physical education teacher in Frederick. Leukemia is a cancer of blood cells. ♦ Survival rates for patients with leukemia range from 20 to 90 percent depending upon the specific type of leukemia and the age of the patient.What Is LeukemIa? 1 Key Po ints ♦ ♦ ♦ ♦ ♦ Cancer is a disease in which cells proliferate without control. He and his wife. Kathy. Cancer is one of the major causes of death in the world. Abnormal gene function causes cancer. Maryland. had two small children. Neil experienced a terrible pain in 11 . One day in 1995. The symptoms of leukemia include fatigue. and easy bruising or bleeding. frequent infections. they lived a good and happy life.

Neil’s . a cancer of the blood. In the case of leukemia. In fact. Bone marrow is the soft tissue located in the large bones of the body. Even though Neil was in critical condition. a situation in which the cancer cells stop dividing and in many cases actually die. Unfortunately. Kathy and Neil left their two small children with their grandparents and Neil was taken to a special cancer hospital in Baltimore. he did not respond by going into remission. The final effort to save Neil was to do a bone marrow transplant. The idea behind bone marrow transplantation is to provide the leukemia patient with normal blood-making cells so that a renewable population of healthy blood cells can replace the abnormal cells. Neil was in the 10 percent of the population of ALL patients who were not cured. The type of leukemia Neil had was acute lymphocytic leukemia (all). a treatment with drugs to kill the leukemia cells. Although Neil underwent chemotherapy. The physicians explained that ALL had a 90 percent cure rate with a twoyear treatment plan. the number of abnormal leukemia cells in Neil’s blood was the highest his doctor had ever seen. His wife noticed that in addition to his back pain.12 Leukemia his back. he was virtually unable to move. At the time of his diagnosis. Kathy and the rest of the family had legitimate reason to hope. Maryland. The bone marrow is a place where blood cells are made. Neil also had a red stripe running down the calf of one of his legs. Kathy took Neil to the emergency room and physicians there explained that the red stripe was due to a blood clot. an abundance of abnormal blood cells are produced. and he was in need of immediate attention. Additional tests revealed more concerning news—Neil had leukemia. a disease seen much more commonly in children than adults. and as a consequence normal blood cell functions such as carrying oxygen and fighting infection are impaired. Cancer is a disease in which cells divide without normal control.

Neil’s family and friends were profoundly shocked. Tumors are abnormal cell masses. such as the circulatory system. cells proliferate only when told to do so. The proteins encoded by the Dna of these genes include growth factors. and cell survival or death. These chemical signals are coded for by two categories of genes. The gene may be changed in such a way . differentiation or specialization of particular cell types. receptors on cell membranes to which growth factors bind. 13 General overview of CanCer One of the major causes of death in the world. Sometimes proto-oncogenes can be altered or mutated so that they no longer function properly. cancer is really a set of more than 100 diseases that all have one thing in common: Cells fail to obey the normal controls that the body has to regulate division. and organ systems. including the nucleus. cells communicate with each other constantly so that they can function together as tissues. crawl. There are hundreds of different proto-oncogenes in all human cells. Ordinarily. In a healthy body. It all happened so quickly. This carefully orchestrated cell society relies on chemical signals that tell cells to divide. and given the initially hopeful predictions regarding Neil’s chances. the cellular behavior elicited is cell division. These proteins encoded by proto-oncogenes comprise a complex regulatory pathway wherein an external signal received by a cell ultimately produces a cellular response. such as the heart. organs. and molecules inside the cells that pass the information collected at the cell surface to specific areas inside the cell. In some cases. such as muscle. or lumps. proto-oncogenes and tumor suppressors. Neil died less than a year after he was first diagnosed.what is Leukemia? father was the donor for the tissue. or die. but even his generous act could not save his son. specialize.

and they must lose the functioning of tumor suppressor genes as well in order for a fully malignant state to develop. meaning that they do not continue to grow in an uncontrolled manner and they remain localized where they originated. When mutations disable tumor suppressor genes. attempting to divide even when it has not been told to do so. thus seriously impairing breathing. even though it is not. In contrast to proto-oncogenes. repair DNA damage. so too will the loss of brakes prevent stopping it. Proto-oncogenes that undergo mutations so that their encoded proteins contribute to cancer development are called oncogenes. an abnormal protein is produced instead. like warts. . Some tumors.14 Leukemia that instead of encoding a functional protein. In contrast. are benign. cells need to have more than one active oncogene. Cancer can be life threatening because tumors can grow so large that they block circulation or damage normal organ functions. trigger cell death. In the case of cancer. Oncogenes can be thought of as analogous to a car accelerator in that when they get stuck “on” due to mutations. cell division cannot be easily stopped. an important mechanism for regulating cell division is lost. a receptor for a growth factor that normally triggers cell division when a growth factor binds to it may be altered so that it is permanently stuck “on” even in the absence of a growth factor. Such a cell is going to lack normal control of cell division. For example. The receptor now acts as if the growth factor is bound all the time. As such. a large lung tumor can crowd out and damage healthy lung tissue. tumor suppressors act like a car’s brakes and prevent cell division from getting out of control. cells of malignant tumors do continue to divide unabated and will spread from their origin by entering the bloodstream and localizing in other tissues in a process called metastasis. For example. and if DNA or cell abnormalities are very serious. Just as having an accelerator stuck “on” will cause a car to accelerate out of control. tumor suppressor genes encode for proteins that halt cell division.

leuKemia is a CanCer of the Blood Cancer can start in cells of any tissue or organ in the body. or  develop into a secondary cancer. die. the cells will either lie dormant. After the tumor cells travel  to the secondary site (extravasion).what is Leukemia? 15 Figure 1. Leukemia is different from most other cancers in that it does not produce .1  Metastasis is the movement of primary cancer cells into the  lymphatic and blood systems to secondary sites.

one complete set is inherited from the mother. C. the other set from the father. The language of DNA is the order of these bases. abbreviated A. Specific sequences of bases direct the cell to make a particular type of protein. deoxyribose. connect to the sugars of the backbone. these cancer cells can proliferate within the circulatory system. These bases stick out from the molecule like little flat plates. and phosphate hook together to make a ribbonlike backbone. The sugar. Just as the identity and arrangement of letters in words indicate meaning—took versus tool versus loot. The chromosomes are composed of DNA and proteins. The genes are inherited instructions of the body that are encoded in the DNA. Regulatory proteins generally help to determine which genes are turned “on” and which are “off. T.” The genetic information present in DNA is a consequence of its chemical structure. Structural proteins help to organize the DNA into wellordered loops and provide a physical scaffold for the chromosome. Four types of bases containing nitrogen. for example—the identity and arrangement of bases provide information to the cell. each cell of the human body contains 46 chromosomes in its nucleus. These 46 chromosomes are actually two solid masses or tumors. And since no growths .16 Leukemia ♦   T he Flo w o F GeneT ic i nF o rm a Tio n Fro m Dn a T o Pr o Tein sets of 23. DNA is composed of several types of chemical building blocks. G. E xcept for eggs and sperm. The proteins associated with chromosomes serve either a structural or regulatory role. Because leukemia is a consequence of the uncontrolled division of certain types of blood cells.

Leukemia is usually detected because a person experiencing one or more of the symptoms detailed above visits his or her physician and is carefully examined. they are sufficiently general that a person might not become especially concerned. . an inadequate supply of these cells renders a person anemic and quite fatigued. and weight loss. cell fragments responsible for blood clotting. frequent infections. headaches. it can be initially challenging to realize that the disease is present. and abdominal swelling. easy bruising and bleeding. Finally.what is Leukemia? or lumps are evident. swollen gums. shortness of breath.” As the disease progresses. so when they are not functioning. A reduction of these blood components causes a person to bruise and bleed easily. leukemia can disrupt the production of platelets. Eventually. Blood tests will also be performed to see whether blood cells are present in healthy numbers and to determine if abnormal blood cells are evident. White blood cells are responsible for fighting infection. The doctor will examine the patient to see if there is abdominal swelling or tenderness as might be expected if the spleen. fever. After all. 1 symptoms and diagnosis While many of the early symptoms of leukemia are noticeable. bone pain. however. a blood-forming organ. was enlarged. or a general lack of “well-being. symptoms can become quite concerning: joint pain. Many of the physical symptoms of leukemia derive from the loss of normal blood cells. the signs become more difficult to ignore: night sweats. a person gets sick more often. swollen lymph nodes. because red blood cells carry oxygen in the blood. chills. For example. there are many reasons one might experience fatigue.

 England.  where he was trained in elocution and read Shakespeare aloud from an early  age. Sedgwick. doctors may evaluate patients by examining bone marrow to see what might be wrong with blood cell development.” in which he and his colleague. Mr. Bennett was a famously talented speaker who expressed  himself in an elegant and dramatic style. Bennett  became interested in pathology.  This contribution to medicine was only one of many that Dr. the study of disease. as an adult. recorded two of the first clinical descriptions of leukemia. Bennett’s enthusiasm got the best of him. D.  in  Which  Death  Took  Place From Suppuration of the Blood. Bennett came from a cultured and intellectual household.1 Leukemia In addition to a physical examination and blood tests. In fact. a rigorous private school. (1812– 1875) I n 1845 Dr. Dr. allows technicians to stain the chromosomes of the leukemia cells with dyes so they can examine them microscopically in order to see whether they sPot liG ht o n CanCer sCie n t is t s J o h n h u g h e s B e n n e t t . Early on. John Hughes Bennett published a celebrated paper entitled  “Case  of  Hypertrophy  of  the  Spleen  and  Liver.  David Craigie.  Born in 1812 in London. A technique called cytogenetics. M .  Sedgwick found out and immediately dismissed Bennett.  and he and another student performed an autopsy without permission. Bennett made  over the course of his eminent career. Mr. . and assisted Sedgwick in many autopsies. He began his medical education  in 1829 as an apprentice to the surgeon. He was educated at Exeter.

  Bennett returned to Edinburgh in 1841. with highest honors and a gold medal in 1837. underneath his somewhat gruff exterior was a kind person. As a person. the specific nature of the damage. and affection for him grew  deeper the longer a person knew him. Molecular techniques may also be used to determine whether the DNA sequence of proto-oncogenes or tumor suppressors has been affected.  He  was  the  first  person to teach histology. He learned  how  to  use  microscopy  in  medical  practice  and  for  medical  instruction. . However. Bennett’s  career  in  Edinburgh  was  very  productive. in 1833 Bennett had the  opportunity to resume his medical studies at the University of Edinburgh  in Scotland. 1 After worrying that he had ruined his future. but because he had a sharp  tongue. He also recognized the importance of examining diseased  organs and tissues with microscopy so that pathologies could be observed.D. Various diagnostic techniques are used in order to determine precisely what type of leukemia is present so that effective treatments can be attempted. He was very successful: He published two papers while still a  student and earned an M.  He worked hard to modernize medicine.what is Leukemia? are damaged and if so.  Bennett continued his medical studies in France and Germany. It was also  in Edinburgh that Bennett observed and described leukemia. some people were frightened by him and did not like him. Bennett was highly respected. Bennett  was beloved by those who were close to him. determined to reform aspects of  clinical practice and education. the systematic study of cells and tissues using  a microscope. arguing against bloodletting and  the overly high does of medicines prescribed to some patients.

 In  fact. ♦  B loo d i s life F rom earliest recorded history. 35. such as headache or fever. there are several forms of leukemia. This medical technique persisted well into the  nineteenth century even though it was not effective for curing disease.000 people in the United States are living with leukemia. Each year. Blood was characterized as the body’s source of  nourishment. overly enthusiastic bloodletting sometimes caused serious harm. Since then. The ancient Greeks thought that health  depended on a harmonious balance of all the body’s fluids. it accounts for more than 30 percent of all childhood cancers.000 new cases are diagnosed. and the survival rates range from 20 to 90 percent depending on the specific type of leukemia and the age of the patient. and physicians in ancient times thought that “disordered”  blood produced fever and illness. When three of the  . In  1799. George Washington complained of a sore throat. However. The remedy for this problem was bloodletting. survival has increased to approximately 50 percent overall. and that certain  physical problems. humans have recognized the fundamental  importance of blood even if they did not understand exactly how blood  functioned in the body. only 14 percent of people with leukemia survived for five years. In 1960.20 Leukemia how Common is leuKemia and Can PeoPle survive? Approximately 200. thanks to the development of new treatments and therapies. or the  removal of “excess” blood.1 Although leukemia is 10 times more prevalent in adults than in children. were caused by a buildup  of too much blood.

what is Leukemia? In fact. blood is used figuratively and literally in the religious  rituals of many faith traditions. This treatment was  not effective: The pope as well as his three young blood donors died. . And a trip to a movie theater will usually offer at least one  entertainment choice that will be awash in blood. The age at which a person develops leukemia depends on the specific type of the disease and can occur in infancy or in later years. the death rate of leukemia is 27 percent higher in men than in women: Of the 22. courage.2 For reasons that are not understood. For example. This idea was so strong  that during the Renaissance the physicians of Pope Innocent VII are said to  have prescribed human blood to save the dying pope.200 children per year in the United States.810 were 21 most respected physicians of the day came to heal the former president.280 people who died of leukemia in 2006. and youth were thought to reside in the blood. In addition to understanding that blood is necessary for the life of the  body. (In addition. Many people practice religions in which blood is an important symbol.  they bled Washington until he died 48 hours later. and fertility rites.  We hold “blood drives” to collect blood from volunteers so that sick people  can be helped. leukemia affects approximately 2. More than 50 percent of leukemia cases are in people older than 64 years. 57 percent of all cases are seen in males and only 43 percent in females. 12. For example. charms. Strength.470 were male and 9. people have also connected it with things that have no relation to  biology. leukemia incidence varies in different populations. Our fascination and relationship with blood are not relics of the past.

and headaches. In fact. The rate of survival depends on the type of leukemia and the age of the patient. Although some other forms of cancer are more common. bleeding.22 Leukemia female. Latinos under the age of 20 years have the highest rate of leukemia. a person suffering from leukemia may experience a range of symptoms including fatigue. bruising.000 new cases are diagnosed each year. Leukemia rates are higher for white and Latino children and lowest in African-American children. approximately 200. a disease in which the normal controls that regulate cell division do not operate properly. can affect people at any age. infections. s u mma ry Cancer.3 It is likely that differences in leukemia among these groups offer clues about the cause and development of this disease. Leukemia is a particular type of cancer that causes the uncontrolled proliferation of abnormal blood cells. The basis for the loss of growth control is a malfunction of specific genes. . Scientists are working hard to try to solve this important puzzle.) Leukemia incidence is also highest in Caucasians and lowest in Native Americans and Alaskan natives. Because the abnormal cells crowd out the normal blood cells.000 people in the United States have leukemia and 35.

♦ Leukemia was first described as a blood cell cancer in the midnineteenth century. exposure to high-energy radiation. ♦ Scientists also discovered that some cancers can be attributed to external causes such as smoking. or exposure to certain chemicals. 23 . ♦ In the nineteenth century. Before scientists understood that cells are the building blocks of living organisms.the hIstory of CanCer 2 and LeukemIa Key Po ints ♦ Cancer has affected humans since the beginning of our existence as a species. scientists recognized that cancer is a cellular disease. ♦ ♦ Cancer is found in species besides humans. they thought cancer was caused by an imbalance of body fluids.

bone tumors and possible nasopharyngeal cancers have been observed in some Egyptian mummies from 5000 b. a type of cancer found today in East Africa.e) are consistent with those that occur in metastatic breast cancer or melanoma. It is extremely likely that cancer was a health problem for organisms long before modern humans evolved. mummified skeletal remains of the Incas. the anthropologist Louis Leakey uncovered an amazing fossil in Kenya. Similarly. Although it was exciting to find bones of pre-human hominids. and even in plants. a text .c. found in Peru and dating back to 2400 bce. a form of skin cancer. as well as in mollusks and other invertebrates. it is described throughout recorded history.24 Leukemia CanCer is older than PeoPle In 1932.e. have lesions characteristic of metastatic melanoma. In another case. produces jaw tumors. cancers can develop in all types of vertebrates. While no one can be completely certain that a lump on a fossilized bone was caused by a malignant tumor. it is interesting to note that Burkitt’s lymphoma. lesions found in the skull of a woman from the Bronze Age (1900–1600 b. In fact. there was something even more special about this particular specimen. including detailed theories of cancer’s causes as well as efforts to treat the disease. CanCer throuGhout history In addition to Leakey’s tantalizing discovery of a fossilized tumor.c. The jawbone exhibited a distinctive swelling that appeared to be the result of a malignant tumor. It was the jaw of an ancient ancestor of humans.1 Because cancer has always been an aspect of the human experience. For example. ancient human remains have also revealed evidence of cancer. The first recorded description of tumors and their treatments is in the Ramayana.

c.d.” in which cancerous tissue was cauterized or burned in order to destroy it. Their written records (from around 1500 b. Hippocrates also advised that no operations should be performed on patients with internal tumors. stomach. rectum. These poisons were believed to be able to kill any remaining bits of tumor that the surgery did not remove. is regarded by many as the first oncologist. Hippocrates described cancers of the breast.e. often characterized as the “father of medicine. because surgery and its complications would likely cause the patient to die sooner than would the tumor. the treatments included cutting out tumors surgically or applying healing ointments containing arsenic. Whereas Hippocrates may be called the father of medicine. belladonna.e). the female reproductive 25 .the history oF CanCer and Leukemia from ancient India (circa 2000 b.” made important observations about cancer. cervix. and nasopharynx. He proposed surgical removal of accessible tumors and treatment of the wound created by the surgery with ointments containing herbal poisons such as hemlock.. He also recorded detailed descriptions of various organs such as the intestines. Hippocrates (460–370 bce). The ancient Egyptians also treated superficial skin cancers with caustic arsenic pastes. He also developed guidelines for treatment. Galen. or arsenic. The ancient Greeks were the first civilization to recognize cancer as a distinct disease. Galen developed great expertise in human anatomy. meaning crab. Galen was the physician for the Roman gladiators. skin. a Greek physician who lived in Rome during the second century a. or cancer specialist.c. The Greeks coined the term carcinoma because they thought that the finger-like projections spreading from a tumor looked like a crab. Among his many responsibilities. It is from them that we get the term carcinoma.) also refer to breast cancers and a treatment called the “fire drill. As a consequence of tending to wounded fighters.

2 Leukemia Figure 2.1  Galen lived from 131 until 231 c.S.  (U.e. National Library of Medicine/National Institutes of Health) .

scientists continued to think that metastasis. They recognized and named epithelial. Even though the descriptions of cancers in those ancient records were quite detailed. muscular. From the time of the ancient Greeks until the 1860s. (continues on page 32) 2 . and connective tissues. no one understood how cancers formed and spread. Rudolf Virchow. stated it clearly: “Omnis cellula a cellula.” meaning that every cell comes from the reproduction of other cells. For example. doctors also lanced swellings or suspicious areas and/or removed blood. reports from the 1600s detail treating ulcerous carcinomas with the extracts of puppies boiled in wine and curing breast cancer by attaching eight frogs at a time to the affected breast and letting them suck the fluids like leeches. Galen’s advice regarding treatment and surgery agreed exactly with that of Hippocrates. scientists observed that the body was composed of tissues that were made of various amorphous materials and different types of fibers. in addition to surgery. Cells and tissues do not form from amorphous liquids and neither do tumors. These ideas regarding how cancer developed led to some treatments that seem useless or even bizarre to us today. Even more bizarre. With no knowledge of cells as the basic building blocks of all living things. By the 1600s. or the spreading of cancer. Physicians thought that these liquids would accumulate in parts of the body that were injured or overused. was due to the traveling of a “bad” fluid to distant parts of the body. people believed that cancers were caused by the accumulation of amorphous or formless liquids in various parts of the body. a German physician and scientist.the history oF CanCer and Leukemia tract. and the breasts. The development of the cell theory in the mid-1800s triggered a complete reconceptualization of science. Both lancing and bloodletting were done to remove these “bad liquids” from the body. neural.

Reasoning that leeches can stop blood clotting because of the chemical hirudin in their blood. By the end of the nineteenth century. and ensured that an appropriate L eeches have been used for thousands of years to remove blood from patients in an effort to treat a wide range of ailments. when medicinal leeches became endangered in Western Europe it became necessary to import them. Egyptian physicians thought that leeches could cure many ailments including fevers and flatulence.000 . apothecary shops (pharmacies) stocked live leeches. Bleeding patients with leeches was not limited to ancient times. used millions of leeches per year. physicians in Paris.28 Leukemia ♦   Medicinal leeches: a n ew Use fo r a n ancie n t t re a t Me n t years ago. France. medical use of leeches fell out of favor as other medical techniques were developed and improved. but the tiny veins kept clotting. Eventually. well into the nineteenth century. The attached leeches promoted blood flow to the area. In fact. This semi-retirement of leeches ended in 1985 with a breakthrough in microsurgery. the surgeon attached leeches around the wound. The height of medicinal use was in the mid-1800s. By that time. and leeching was considered to be the most precise method because of the reputed ability of leeches to distinguish between “good” and “bad” blood. In ancient India. A surgeon was trying to reattach an ear to a five-year-old patient. removed excess blood. bloodletting was done to treat illness. He knew that pooled blood around a wound endangers tissue survival. More than 5.

 medicinal leeches are used to help speed the healing of skin  grafts and finger reattachments. to be used as medical devices. the tiny veins had the opportunity to regenerate and reconnect circulation. .  As  a  consequence.  ( Bill Beatty/Visuals Unlimited) amount  of  oxygenated  blood  was  always  present  near  the  wound. The ear was saved. the  Food and Drug Administration (FDA) cleared the first application for medicinal leeches. In 2004.the history oF CanCer and Leukemia 2 Figure 2. Hirudo medicinalis.2  Today.2 Leeches have proven effective in healing skin grafts and aiding plastic  or reconstructive surgery including reattachment of fingers.

 your prognosis is excellent. Because the pain is difficult to tolerate.30 Leukemia sPot liG ht o n CanCer sCie n t is t s : g i ova n n i B a t t i s ta M o rg a g n i .S. D.  Because  you  are  in  good  health  generally. they  think you might be suffering from  appendicitis. Once you arrive. based on the symptoms you are presenting. M. Middle  Ages  probably  would  have  elicited  a  diagnosis  that  the  individual was possessed by an evil  . P h .  They  conduct  additional tests to verify this diagnosis. How is it that physicians can  make  accurate  diagnoses  from  a  physical examination of the body?  The  symptoms  of  appendicitis  displayed  by  someone  during  the  Figure 2. physi- cians examine you and.D.  the  treatment  will  be  surgery  to  remove  the  inflamed  appendix.3  Giovanni Battista  Morgagni. you decide to  go to the emergency room for medical attention. You will recover fully. National Library of Medicine/National Institutes of Health). . ( 1 6 8 2–1771) I magine waking up in the middle of the night with an intense pain on  the right side of your lower abdomen.  (U. If it turns out to be correct. Maybe you are running a fever  and feel nauseous.

 and prognosis of disease depend  on knowing the pathological changes in anatomy. Thanks  to him. Born in 1682.  He  decided  to  become an anatomist and devoted himself to pathology. and techniques that could reveal hidden anatomical  pathologies in living patients.  Italy.  in  1698.  Seats and Causes of Disease Investigated by Means of Anatomy. physicians and scientists turned their attentions to developing  new tools.  He  is  the  first  person  ever  to  connect  what  he  saw  in  the  cadaver  to  clinical  findings  for  that  individual.  Morgagni was an excellent teacher and a prolific writer. Morgagni insisted that physicians needed to think of disease in  terms of localized pathologies rather than body fluid imbalances. treatment. Morgagni revealed his scholarly talent even as a boy. a five-volume work that is the foundation for modern pathological  anatomy.  Morgagni  describes  the  observations  and  findings  he  made  in  640  autopsies. where he remained for the rest of his life. Morgagni’s undeniable ability enabled him to advance into professional positions of increasing  responsibility and eminence.  and  Ph.  By  1701  Morgagni  had  earned  his  M.  the  treatment would be bloodletting and if the appendix ruptured. He  started  his  medical  studies  in  Bologna.  the  most  influential  was  his  concept that the diagnosis. By 1715 he was named Chair of Anatomy at the  University of Padua. In 1761 he published  his  masterpiece. methods.”  In  either  case. Among his  many  important  findings  and  discoveries.  It  is  thanks  to  Italian  physician  and  scientist  Giovanni  Battista Morgagni that we no longer take such an ineffective and potentially  dangerous approach to diagnosis and treatment.the history oF CanCer and Leukemia 31 sprit  or  that  the  bodily  fluids  were  not  “balanced.  In  this  treatise.:  he  was  only  19  years  old. .D. the patient  would  die.D.

  the  study  of  diseased  cells and tissues. He presented evidence that the tumor was sPot l iG ht o n Ca nCer sCie n t is t s : r u D o l f v i rc h ow. in 1843. Virchow’s early education revealed his great promise. By the late 1860s scientists were able to do careful microscopic studies of cells and tumors in order to learn more about cancer.  in  1848  he  was  appointed  by  the  government to investigate an outbreak of typhus fever in the country. he received free medical training in Berlin.  Virchow  noted  that  improperly  functioning  sewers.  Virchow’s report blamed social conditions and the government for the  state  of  affairs  that  led  to  the  outbreak.  As a consequence.32 Leukemia (continued from page 27) Cancer cells are produced by other cells.  and  crowded  conditions were instrumental in the spread of the disease. Germany. Born in 1821 to a family of mod- est financial means.D.  For  example.  Virchow began his medical studies in 1839 and received his M. Not only did  . In 1869 Wilhelm Waldeyer.D.  Particularly  fascinated  by  pathological  histology. M . (1821– 1902) A spects of our understanding of the cellular basis for many diseases. and metastasis is due to the migration of these cells to other parts of the body. Virchow was an ardent  social  reformer. a German scientist.  In addition to his scientific and medical work.    including cancer. published a paper in which he detailed the pathology of breast cancer. Virchow published a paper in 1845 that contained one of  the earliest pathological descriptions of leukemia. Rudolf Virchow.  a  lack  of  clean  drinking  water. derive from the pioneering work of the German pa- thologist and physician.

. Cellular Pathology as Based Upon Physiological and Pathological Histology. Waldeyer even observed that cancer cells could stimulate the growth of capillaries. all the while treating patients and doing scientific  research. he observed that the tumor spread into the local area and then to distant sites due to tumor cells that had entered the bloodstream and were carried elsewhere. Virchow stayed active  in his reform efforts.  an  entire  pathological  institute  was  built  for him at the University of Berlin. or small blood vessels.the history oF CanCer and Leukemia epithelial in nature and had in fact arisen from normal epithelial tissue. This paper was astonishing in its detail and accuracy. Moreover. With this publication. it still holds up today.  Virchow  emphasized  clinical  observation. 33 government officials ignore his recommendations for alleviating these  problems. Also.  physiological  experiments  using  laboratory  animals. Among  Virchow’s  many  accomplishments  was  his  recognition  that  outside stimuli affected cells.  In  1858  Virchow  published  one of the most important books in modern medicine.  and  pathological  anatomy  especially  at  the  microscopic  level.  In  his  research. In 1856 a chair of pathological anatomy was established for    Virchow  in  Berlin—in  fact. including cancer. and that diseased cells come from already  diseased cells. he understood that cancer cells came from previously  healthy  cells. but they also suspended Virchow for two weeks and then reinstated him in a demoted position.  Virchow firmly established that the cell was the most important aspect of  disease pathologies. Nevertheless. including  cancer cells. He realized that all cells arise from other cells. which would connect to the tumor and bring it blood to support its growth. Virchow worked there for the rest of  his life.

and radioactive dust from mining. Other potential workplace carcinogens include X-rays. asbestos fibers. warned that inhaling snuff. For example. In addition to occupational cancers. This was the first example of a cancer caused by a workplace exposure to a carcinogen. Similarly. tight clothing. an English physician. These differences in . breast cancer rates are higher in North America and Western Europe than in Japan. or cancer-causing material. and physical injury. From ancient times to the twentieth century. He even encouraged the public display of lungs blackened by tobacco smoke. a medical study done in Chicago in 1907 showed that cancer rates were higher in meat-eaters—individuals of German. King James I of England’s A Counterblaste to Tobacco described the evils of smoking and the health problems it produced. people began to suspect correctly that certain human activities increased the likelihood of cancer. Irish. or Scandinavian origins—than in pasta. However. cancer has been attributed to causes that include evil spirits and demons. certain chemical solvents. finely ground tobacco. In 1604. by the time of the Renaissance. it has taken a long time to understand something about the potential causes of cancer.or rice-eaters—people originally from Italy or China. The relationship between exposure to chimney soot in chimney sweeps and the development of scrotal cancer in these individuals was well documented by the English surgeon Percival Potts in 1775. Scientists also observed that specific cancer incidences varied geographically. In 1761 John Hill. caused nasal cancer. where the rates of stomach cancer are greater. emotional turmoil. For example.34 Leukemia ideas aBout Causes It took thousands of years for scientists and doctors to observe and describe the cellular events that occur in cancer. other patterns of cancer related to human activity were discovered. The problem was so serious that doctors entertained all ideas in hope of preventing and curing this disease.

two other French physicians described similar cases in which the deceased individuals had complained of fever and weakness. Finally. scientists explored the possibility that cancer was caused by an infection. weakness. In 1839. They also had enlarged spleens and white material in their blood. Perhaps the most startling example of a human behavior related to cancer is that of tobacco smoking. A normal spleen weighs less than onehalf of a pound. Although there are some viruses. the man’s blood was filled with white material that Velpeau identified as pus. it does not produce a solid tumor. and other pains. Velpeau weighed the deceased man’s enlarged spleen. The likelihood of developing a smoking-related cancer increases the longer and the greater the number of cigarettes one smokes. bacteria. As consequence. These physicians did not think this white material was pus but suggested that it was comprised of white blood cells. only approximately 5 percent of cancers can be attributed to infection. Also. In 1827. and even flatworms that can cause certain human cancers.the history oF CanCer and Leukemia cancer incidence are likely due to differences in diet and lifestyle. it was difficult for doctors and scientists to recognize that leukemia was actually a malignant cancer.3 35 history of leuKemia Because leukemia is a type of cancer that develops from blood-forming cells. In stark contrast. it was 10 pounds. Cigarette smokers have a dramatically higher incidence of lung and other forms of cancer than do nonsmokers. . headaches. the French physician Velpeau described what he observed in the autopsied body of a man who had complained of fever. more than 20 percent of cancers detected in people in developing countries are caused in this way. in developed countries such as the United States.

In Edinburgh.4  This colored scanning electron micrograph (SEM) shows a blood  sample from a person with chronic lymphocytic leukemia (CLL).3 Leukemia Figure 2. The sample  contains a far greater number of white blood cells (blue) than would a sample  from a healthy person. . although they did not understand that they were observing a type of cancer.  In 1845 three physicians and scientists independently determined the correct nature of the white material in the blood.

Rudolf Virchow in Germany identified “weisse Blut. Physicians really had no idea how to treat the disease until many years later.the history oF CanCer and Leukemia Scotland. Finally. Dr. and effort was devoted to improving diagnosis. it has been a health concern since the dawn of humanity. Leukemia. also in Edinburgh. Greece. John Bennett autopsied a man whose spleen was enlarged to more than seven pounds. autopsied a man possessing a nearly eight-pound spleen. and prevention. based on a closer. treatments. Because leukemia was not recognized as a cancer until the mid– nineteenth century. a cancer of blood cells. A direct examination of his blood also revealed an abundance of white blood cells. and cures for this specific disease really do not exist. India. was more difficult to recognize because solid tumors or lumps do not generally form. Once people understood that leukemia was a blood cancer.” what we call leukemia—an imbalance between white blood cells and red blood cells. Ancient records from Egypt. Craigie. The clinical description of leukemia was not recorded until the mid–nineteenth century. . Dr. and Rome describe the existence of various forms of cancer as well as efforts to treat the disease and understand its causes. Bennett examined the man’s blood microscopically and observed an abundance of white blood cells. research. 3 su mma ry Cancer is not a modern phenomenon. Similarly. older ideas about causes. a great deal of thinking. direct observation of blood. treatment.

BLood CeLL deveLopment and funCtIon

3

Key Po ints
♦ ♦

Blood consists of blood cells suspended in a liquid called plasma. The major components of the blood cell population are erythrocytes (red blood cells), leukocytes (white blood cells), and platelets.

♦

There are many types of leukocytes, each performing different functions.

♦ ♦

Blood cells originate from a self-renewing population of stem cells. Leukemia symptoms result from the inability of blood cells to perform their normal functions in the body.

Tom Kochanowicz, a 38-year-old man from Omaha, Nebraska, went to see his family physician for a checkup. Tom was feeling tired and he 3

BLood CeLL deveLopment and FunCtions had been getting colds more frequently. Also, he had noticed that if he cut himself shaving, it took a little longer than usual for the bleeding to stop. At the time of this checkup the doctor detected a worrisome lump in Tom’s side—perhaps an enlarged spleen or lymph node. Additional tests revealed that Tom was suffering from a slow-growing form of leukemia. The abnormal cells were gradually overwhelming the normal cells in his blood. An inadequate number of normal cells were able to form. As a consequence, Tom experienced a variety of symptoms, each of which could be attributed to the failure or depletion of particular types of blood cells.

3

how do Blood Cells form and develoP?
Blood is actually a type of tissue in which the different types of cells work together to perform specific functions but are not physically connected. In fact, blood cells are suspended in a complex liquid called plasma. In a sample of blood, 55 percent of blood volume is plasma and 45 percent is composed of cells. The plasma itself is 90 percent water with the remaining 10 percent containing materials such as oxygen, carbon dioxide, nutrients, hormones, waste products of metabolism, proteins important for blood clotting and immune responses, and electrolytes needed for water balance and cell membrane function. The blood cell population also has several different components: erythrocytes, or red blood cells; leukocytes, or white blood cells; and platelets. Unlike some cells, such as muscle or brain cells, blood cells do not live for long time periods. For example, erythrocytes have a lifespan of 120 days and leukocytes live from hours to weeks, depending upon the specific type of leukocyte. Once cells have worn out, they die, the useful components of the resulting debris are recycled, and waste products

40

Leukemia

Figure 3.1  The main components of blood are plasma, leukocytes and  platelets, and erythrocytes. Plasma, the most abundant component, makes up  about 55 percent of blood’s volume. Erythrocytes make up about 45 percent of  blood’s volume. Leukocytes and platelets make up less than 1 percent of blood’s  volume.

All blood cells do indeed originate from a pluripotent stem cell. old and damaged blood cells are easily replaced.BLood CeLL deveLopment and FunCtions are eliminated from the body. Myeloid stem cells are located in the bone marrow. and the body. The process of blood cell formation is called hematopoiesis. When a pluripotent stem cell divides. megakaryocytes (these produce platelets and are important for blood clotting). they can undergo cell division and make cells that can ultimately form different types of blood cells. Lymphoid and myeloid refer to two different lineages or branches of the blood cell “family tree. Pluripotent means that these cells are not fully specialized or differentiated. A closer look at how blood cells form reveals a complicated picture. thus replenishing the supply of their own population. All blood cells. or a lymphoid stem cell. In fact. The types of cells that are made from this line include erythrocytes. originate from pluripotent stem cells. the resulting cells can be another pluripotent stem cell. For example. and five types of leukocytes: basophils. Because the body makes new blood cells continuously throughout a person’s life. or a myeloid stem cell. stem cells can also make new stem cells. depending on the instructions received from other cells. the spongy material found inside bones. their local tissue environment. which are located in the marrow. the body sends a signal to the bone marrow that directs the stem cells to make leukocytes.” Let’s follow the specific pathways of the myeloid and lymphoid lineages. This blood production factory works throughout a person’s life because in addition to producing offspring that will ultimately become blood cells. no matter what type. which help fight the infection. when a person is ill with an infection. Blood cells form and develop in the bone marrow. eosinophils. neutrophils. 41 .

42 Leukemia .

Oxygen is essential for the functioning and survival of all cells and organs. and T lymphocytes.  . running. This means that our body contains approximately 5 trillion erythrocytes in the five liters of blood each of us possesses! The principal job of red blood cells is to transport oxygen. which allows more oxygen to reach muscles and organs. oxygen delivery can be greatly diminished. Exercising. hemoglobin. These cells can produce three types of leukocytes: nk or natural killer cells. All of the leukocytes fight infection in ways specific to their cell type.1 Thus oxygen. and monocytes (these become macrophages. is delivered to every organ and cell in the body. Because each hemoglobin molecule can carry four oxygen molecules. It is also important for the body to have adequate oxygen so that sufficient energy will be available to power physical exertion. or doing anything that is physically demanding increases the breathing rate. carried by the erythrocytes.BLood CeLL deveLopment and FunCtions dendritic cells. When healthy erythrocytes are in short supply.2  (opposite page)  This diagram shows the process of the formation and differentiation of stem cells. each red blood cell can transport up to 1 billion oxygen molecules. Figure 3. A person with leukemia may tire or fatigue easily if the abnormal cells are outnumbering normal erythrocytes. 43 funCtions of healthy Blood Cells and the imPaCt of leuKemia Numbering between 5 and 6 million per milliliter of blood. B lymphocytes. In fact. each erythrocyte contains 250 million molecules of the oxygen-binding protein. erythrocytes are by far the most abundant type of blood cells. called hematopoiesis.) Lymphoid stem cells are also located in the bone marrow. which are important for removing bacteria and dirt.

D. This work was essential for all future research in hematology. one milliliter of blood contains 250.  After  his  cell-staining  studies. histology. (1854– 1915) A lthough trained as a physician. live only 5 to 9 days. in 1878. Megakaryocytes shed small. Platelets are not exactly cells. Ehrlich earned his M.D. immunology. and somewhat timid man. They are located throughout tissues of the body and are sPot liG ht o n CanCer sCie n t is t s : P a u l e h r l i c h .  Ehrlich did not want to witness the suffering of patients or to inflict pain  an enormous number of patients in his day and built the foundation for  treating them. thus making previously invisible structures easy to see with a microscope.000 to 300. M . the accomplishments of his life’s work helped  breakthroughs that ease sickness today.44 Leukemia Next in order of relative abundance in the blood are platelets.  Ehrlich  turned  his  . Nevertheless. Paul Ehrlich preferred medical research    to clinical practice. A sensitive. He published  a  remarkable  thesis  that  described  his  pioneering  methods  for  staining  animal cells and tissues with colored dyes. These fragments. They are produced by huge cells. megakaryocytes. Born in Germany in 1854. which are from the myeloid lineage. Ehrlich continued this work  and ultimately developed methods to stain blood cells so that all types  could be identified.  Ehrlich  also  tackled  two  other  problems  that  are  significant  to  our  understanding  of  leukemia  and  the  treatment  of  disease. very short-lived fragments. modest. and oncology.000 of these cellular elements. or platelets. In  addition  to  this  area  of  research.

 he was awarded the Nobel Prize in 1908 for his “side-chain  theory” of antibody formation. These antibodies  rendered the mice resistant to the poison. and when bruises do happen. or white blood cells. Finally. Ehrlich’s ideas about chemotherapy have been adapted  effectively to develop drugs for other types of infectious disease.BLood CeLL deveLopment and FunCtions essential for blood clotting. or white blood cells. as well  as cancer in general and leukemia in particular. they are larger because the internal bleeding that causes bruising can persist. Ehrlich succeeded in developing a  treatment for syphilis.  He  reasoned  that  chemicals  could  be  developed  that  would  attack  infectious  organisms  specifically without harming the host.  Ehrlich  also  founded  the  field  of  chemotherapy. bruises occur more readily. the mice produced antibodies in their blood. a sexually transmitted disease that had long been a  scourge on society. the least numerous but certainly not least important blood cells are leukocytes. Ehrlich was a very energetic and careful experimentalist who enjoyed  the affection and respect of all who worked with him. He was kind and  devoted to his wife and two daughters. Perhaps the only complaint anyone  ever  had  about  him  concerned  his  lifelong  habit  of  smoking  25  strong  cigars each day. He died in 1915 after suffering a stroke. Ehrlich called this phenomenon  immunization. cuts bleed for longer time periods. When platelets are in short supply due to leukemia. In 1891  he discovered that when he exposed mice to plant poisons such as ricin  or abrin. . One milliliter of blood contains 45 attention to the function of the leukocytes.

 or erythrocytes  ( Dr. between 50 and 70 percent are neutrophils. Another 20 to 50 percent .3  Red blood cells. Of those. a type of leukocyte that eats invading bacteria and digests them with corrosive chemicals. Fred Hossler/Visuals Unlimited) between 5.000 white blood cells.000 and 9.4 Leukemia Figure 3.

4  Platelets are essential for blood clotting and wound healing. specialized cells that produce antibodies. meaning they will hungrily eat large numbers of invading bacteria. Another 1 to 5 percent of the leukocyte population are eosinophils.    ( Dr. chemicals that recognize specifically and mark for destruction cells or bacteria that are foreign to the body. Macrophages are especially voracious phagocytic cells. Dennis Kunkel/Visuals Unlimited) are lymphocytes.BLood CeLL deveLopment and FunCtions 4 Figure 3. Monocytes comprise 2 to 8 percent of the leukocyte population and develop into macrophages in tissues. which release chemicals to .

Finally. and it signals other leukocytes to come streaming to the site. leuKemiC stem Cells The notion that cancers might arise from “leftover. leukocytes. chemicals that trigger inflammation. The myeloid and lymphoid lineages have the capacity to start with nonspecialized cells and to have them become. cells get sidetracked in their development and continue to divide without ever maturing. Basophils are also responsible for the symptoms experienced by those who suffer from allergies. the immature cells that accumulate may not be able to carry oxygen efficiently. They based their theory on microscopic observations of tissues from fetuses and their similarities to certain types of tumors. or platelets produces serious physical consequences. release histamines.” undifferentiated embryonic tissue dates back more than 150 years to the ideas of Rudolf Virchow and Julius Cohnheim.4 Leukemia damage parasites such as worms. Inflammation causes tissue to swell and to become red and warm. With leukemia. they also crowd out the normal cells that might be able to perform these tasks. Given the range of important functions for which blood cells are responsible. By overwhelming the blood cell population. differentiated cells. Depending on the specific type of leukemia. Leukemia exerts this impact because the disease is the consequence of the overproduction of immature blood cells that do not function properly. fight infection. basophils. only 0. both cancer cells and embryonic cells underwent cell division and were unspecialized or . over the course of their development.1 percent of the population. After all. The notion that cancer cells might be similar to embryonic cells was very appealing. two German scientists. or help blood to clot. it is no surprise that interference with erythrocytes.

5  White blood cells.BLood CeLL deveLopment and FunCtions 4 Figure 3. Phillips/Visuals Unlimited) . or leukocytes  ( Dr. David M.

 In addition.  and  even  cancer  cells. In addition to the vessels. Fluid enters the lymphatic system by diffusing into small lymph capillaries. and the remaining 15 percent is returned to  the blood by lymph vessels.  tonsils. keep a reserve of “embryonic-like” cells in reserve—stem cells.  Pathologists  use  cell  staining.  they filter the lymph and are populated by white blood cells that attack  viruses. the body also has a series of lymph vessels called  the lymphatic system. some tissues.  Similarly. For this reason when a person has an infection. When blood enters a capillary.50 Leukemia undifferentiated. Like the cells seen in embryos or cancer.  The  lymph  fluid  is  similar  to  the  liquid  found  in  the  spaces  between  cells. the smallest type of  blood vessel.  bacteria.  Eventually all of the lymph re-enters the blood circulatory system via large  veins located above the heart. Also. it loses fluid into the surrounding tissue. analyzing lymph nodes that are “downstream” from a tumor can help determine  whether  metastasis  has  occurred. which is composed of blood ves- sels and the heart. such as blood.  and  appendix  trap  foreign  materials  and  fight  them  with  white  blood  cells.  the  spleen. ♦  Th e Ly mphaTic SySTem I n addition to the circulatory system. Lymph nodes are located along the lymphatic vessels. lymph nodes may become tender and swollen. the lymphatic system also contains specialized tissues. and in some cases  cancer.  . The capillary recaptures 85 percent of this fluid.  Blood  capillaries  and  lymph  capillaries  are  located  together. stem cells can keep dividing and they do not differentiate.

 and molecular techniques to detect cancer cells that have  been trapped in lymph nodes. As we now realize. Pappenheim was correct. .BLood CeLL deveLopment and FunCtions In 1917 Arthur Pappenheim was the first scientist to hypothesize that normal blood cells come from a stem cell population. and it may be that aspects of Virchow and 51 Figure 3.6    microscopy.

52

Leukemia Cohnheim’s theory were as well. It is likely that all cancers derive from small populations of “cancer stem cells” and that the leukemia itself originates from a leukemic stem cell (lSC). In 1973 Ernest McCulloch isolated myeloma cells from a mouse. Myeloma is a type of cancer affecting lymphocytes. McCulloch examined the cells closely and found that only 1 out of 100 to 1 out of 10,000 could grow outside the mouse’s body in a culture dish the way that cancer cells generally can.2 McCulloch concluded that only a small proportion of these cancer cells behaved like stem cells, meaning they could divide and produce more cancer cells. In 1985 Jim McGriffin made similar observations in humans. McGriffin was studying human leukemia cells and demonstrated that only a small proportion of them were responsible for generating the other leukemia cells. In other words, they were behaving like stem cells.3 The idea that cancer cells originate from a single cell was reinforced by Philip Fialkow’s demonstration that leukemic cells are clonal in origin. He examined the DNA of the leukemic cells and observed that it was identical, meaning the cells were the clone of a single original cell. Finally, in 1997 John Dick and his colleagues demonstrated the existence of a leukemic stem cell (LSC). The discovery was met with great excitement and it opened up new areas for research. Scientists are trying to understand the biology of LSC in particular and how it compares with that of normal blood stem cells, with the objective of identifying new treatments.

s u mma ry Blood cells develop in the bone marrow, a spongy tissue found inside bones. The three major components in the blood cell population are erythrocytes, leukocytes, and platelets. Erythrocytes are important for

BLood CeLL deveLopment and FunCtions transporting oxygen in the body; leukocytes are part of the immune system and help fight infection; and platelets are cell fragments that participate in blood clotting. All types of blood cells originate from pluripotent stem cells. There are many types of leukocytes but the broadest categories are those arising from the lymphoid lineage and those from the myeloid lineage. Leukemia cells originate from their own type of abnormal stem cell, called a leukemic stem cell (LSC).

53

LeukemIas are not aLL

4

the

same

Key Po ints
♦

There are four major types of leukemia: acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML).

♦ ♦ ♦

Leukemia is the most common type of cancer in children. ALL accounts for 75 percent of childhood leukemia cases. CLL is the most common type of leukemia in adults in North America and Western Europe.

♦ ♦

AML is generally more deadly than other types of cancer. CML is associated with the presence of the Philadelphia chromosome in leukemia cells.

On February 24, 1841, Peter Campbell was admitted into the Royal Infirmary in Edinburgh, Scotland. Mr. Campbell was 30 years old and a 54

Campbell with leeches. By March 25. Mr. Again. Doctors bled him one more time on March 28. Although doctors were not sure what was wrong with Mr. and unable to eat. This material resembled pus that could have collected due to an infection. and that are surrounded by inflamed tissue) was strong evidence that no infection had occurred. He had noticed the swelling in his abdomen four months previous to this visit but it had not hurt. doctors bled Mr. Campbell worsened. Second. the abundance of the “pus” and the absence of any abscesses (pockets containing pus and dead cells. Mr. this treatment did not help. Campbell was very weak. his principal symptom being sore joints. Campbell’s body on April 3. He went to the infirmary because he felt weak and had a swollen abdomen. Unfortunately. so he had not sought medical help. Mr. fevered. and tried to make him comfortable. the abdominal swelling was due to an enlarged spleen. Doctors autopsied Mr. Campbell had started to feel ill about six weeks earlier. Campbell. 55 . 3. over the next two days. Mr. he made cloth on a loom. On March 26. and his pulse was 104 beats per minute (a normal pulse ranges from 60 to 70 beats per minute). this treatment had no effect. Campbell reported that he had experienced “night sweats” and that he found it difficult to breathe when he exerted himself. He had a fever and his pulse was much faster than normal. but doctors could find no evidence that an infection had been present. Recall that a normal spleen weighs less than half a pound. hoping to remove harmful substances in his blood. He died on April 1. By March 30. First. In fact. Mr. the spleen and blood vessels throughout the body contained an abundance of white material. observed him. Campbell’s weighed 7 pounds. they kept him in the hospital. and nor did anything else that doctors tried.Leukemias are not aLL the same weaver by trade. In fact. Mr. Campbell was complaining of severe pain in his head. His illness had killed him quickly. Two observations are particularly noteworthy. they removed 14 ounces of blood.5 ounces.

physicians today would also collect blood to study and probably evaluate bone marrow samples to see whether leukemic cells were present.” Neumann discovered that blood cells are  produced in bone marrow. In addition to the types of information collected from examinations of him while he lived and after he died. Campbell suffered from leukemia.D. Berlin. because. M .  In  1859 Neumann was appointed a lecturer in medicine. as in the case for cancer in general. chronic lymphocytic leukemia (Cll). He also earned his M. Neumann was born in 1834 and earned his degree from the University  of Königsberg in 1850. leukemia can be divided into four major types: acute lymphocytic leukemia (ALL). in 1855 and then continued his training in labs in Prague.  Neumann  studied  under  the  guidance  of  Rudolf  Virchow. brother.5 Leukemia Looking at the description of this case with the benefit of twentyfirst-century knowledge. sPot liG ht o n CanCer sCie n t is t s : e r n s t n e u M a n n . and if so the type or types of these cells. (1834– 1918) P erhaps it is because he was a painfully quiet man or maybe it was being  in a family where his son. we can readily hypothesize that Mr. and father were famous mathemati- cians that prevented the Prussian scientist and physician Ernst Neumann  from enjoying the place in history that he so richly deserves. and in 1866 he was  . Depending on the specific blood cells affected. leukemia is not a single disease.  In  Berlin. and then back in Königsberg.D. Referred to  as the “father of hematology. Physicians would also determine what kind of leukemia was present.

Leukemias are not aLL the same acute myelogenous leukemia (aml). In 1868 Neumann described his observations of the bone marrows of  humans and rabbits. Neumann concluded that red blood  cells are made and develop in the marrow. This idea was ahead of its time and was not  accepted by his contemporaries. and chronic myelogenous leukemia (Cml). increased infections. mature red blood cells in mammals do not have nuclei. and treatment. Moreover. The symptoms of all types of leukemia share similarities such as fatigue. Diagnostic procedures are also alike for all leukemia types. doctors collect blood and bone marrow to determine what specific type of leukemia cells is present. and easier bruising. He discovered that the marrow contained red  blood cells that had nuclei.  Neumann postulated that a single type of renewable stem cell gave rise to  all of the cells of the blood. acute is rapid and chronic is slow. Subsequent to this discovery. 5 promoted to Professor of Pathology. Consequently. What does differ quite a bit among the various leukemias is typical age of onset. In contrast. . Acute and chronic refer to the rate at which the disease advances. Neumann  continued  his  research  throughout  his  life. He had squeezed the marrow out of the bones and  observed it microscopically. He died in 1918. respectively.  making  several  other discoveries including that of myelogenous leukemia. Lymphocytic and myelogenous indicate whether the leukemia cells originated with the lymphoid or myeloid lineages. He remained in Königsberg for the  rest of his life. he  revealed that white blood cells are also produced in the marrow. prognosis or predictions about the course of the disease.

The causes of ALL are not well understood. of 22. Diagnosis of ALL generally occurs between the of ages 2 and 8. This technique allows physicians to determine exactly what kind of lymphocyte is abnormal.490 had suffered with ALL. more than 95 percent of CLL patients are more than 50 years . Exposure to high doses of radiation increases risk.000 people are diagnosed each year in the United States alone. Adult survival ranges from 40 to 65 percent. In fact. accounting for approximately 2 percent of all cancers in the United States. immunophenotyping is also done. the most common type of cancer in children and ALL accounts for 75 percent of childhood leukemia.5 Leukemia aCute lymPhoCytiC leuKemia (all) Acute leukemias are generally rare.000 new cases of ALL are diagnosed in the United States. survival rates are as high as 90 percent. the peak incidence is at 4 years. Treatment of children with ALL has been very successful. ALL is one of the few cancers that occurs in lower numbers in poor people. 1. adults with ALL fare less well than children.2 ChroniC lymPhoCytiC leuKemia (Cll) CLL is the most common form of leukemia in adults in Western countries. Knowing the precise nature of the ALL is important for providing effective treatment. however.1 The diagnosis of ALL depends on physical examination of the patient as well as close examination of the blood and bone marrow. Unfortunately. CLL is quite uncommon in individuals before the age of 45.280 people who died of leukemia. If ALL is suspected. This disease occurs more commonly in children and young adults than in older people. More than 10. Leukemia is. Each year approximately 4. as does living in a developed country or being socioeconomically advantaged. In 2006.

Inc.1  Acute lymphocytic leukemia (ALL) causes the excessive production of immature white blood cells (purple).  white blood cells. the doctor will order additional tests to examine the bone marrow to determine exactly what type of lymphocyte is involved. and platelets. This excess of immature white  blood cells limits the space in the bone marrow for normal red blood cells. Most CLL patients are diagnosed after a routine checkup. Because CLL comes on slowly and gradually. The resulting lowered levels of these normal  cells causes the various symptoms of the disease. and also to have cells analyzed to see whether chromosomes are damaged in any way. The physician notices an enlarged lymph node and enlarged spleen and consequently orders a blood test to see if the blood cells are normal. If this test reveals an overabundance of leukocytes.Leukemias are not aLL the same 5 Figure 4.  ( Biology Media/Photo Researchers. symptoms can easily go unnoticed. .) old.

 This form of leukemia  is most often found in the elderly.  ( Steve Gschmeissner/Photo Researchers. but they have have identified several risk factors. CLL is more common in males and in white people of European ancestry than in individuals of Asian ancestry.0 Leukemia Figure 4. Inc.2  This colored scanning electron micrograph (SEM) shows white  blood cells from a patient with chronic lymphocytic leukemia (CLL). In China. this form of  leukemia causes the excessive production of lymphocytes. CLL accounted for only 4 to 6 percent of all leukemias among hospitalized patients in Beijing. A comparison of CLL incidence in China and the United States underscores the role of ethnicity.4 Furthermore.) Scientists have not determined the causes of CLL. .3. For example. whereas 30 percent of adult leukemia in the United States is CLL.

For example. More specifically. herbicides containing 2. Put another way. If treatment becomes necessary. CLL was the culprit in 600 cases. is associated with an increased CLL risk. Alone. 5-T and 2. The initial bone marrow sample and biopsy serves as a baseline against which other samples can be compared to make sure the disease is not out of control. the herbicides 2. CLL shows the highest family incidence of any of the major blood cancers. 4. this factor will not cause CLL. Additional studies that examined the family patterns of CLL incidence suggest that there is a hereditary factor that affects the susceptibility to developing CLL. 4. In many cases of CLL. a white adult from the United States who moves to Beijing will not enjoy the same lower risk for CLL that Chinese people do. Of 22. Because CLL generally advances slowly. 4-D are readily available for sale not only to farmers but also to shoppers at the local gardening store.Leukemias are not aLL the same studies of migrating human populations show that ethnic groups retain their risk for CLL associated with their geographical origin rather than assuming the risk associated with their new location. Also. phenoxy. but if a person has it and is exposed to additional risk factors. Although 2. most physicians will take a “watchful-waiting” approach to treatment. one class of herbicides. Other risk factors include exposure to pesticides or the chemicals used in farming. The survival rate for CLL is approximately 75 percent. 4-D are candidates for increasing the risk of CLL. the likelihood of developing CLL increases. it is better for the patient to “maintain” the disease rather than undergo radiation or chemotherapy treatments that might diminish the quality of life without eliminating the cancer. that initial bone marrow biopsy will come in handy as a baseline to check whether treatments are working.280 people who died of leukemia in 2006. physicians will take action.5 1 . 5-T use has been restricted by law.

and identifying the type is essential for predicting the course of the disease and treating the patient effectively.000 new cases are diagnosed per year in the United States. The risk of AML increases with age. The median age of diagnosis is 65 years. The idea behind the approach is that if cancer cells could be forced to mature and differentiate.6 AML occurs when there is disruption in the function of a transcription factor. AML incidence is 1 in 100. whereas monocytes are a type of white blood cell that develops into macrophages. meaning that they eat debris and invading microorganisms that enter the body. The likelihood of death due to AML is also related to age. AML is the most deadly. Macrophages are phagocytic cells. One type of treatment that has shown hopeful signs of success is differentiation therapy. Compared to other types of leukemia.to 34-year-olds. but it reaches greater than 50 percent for AML patients under the age of 15 years.280 people who died of leukemia in 2006. The goal of differentiation therapy is to regulate genes in . There are eight different subtypes of AML.2 Leukemia aCute myeloGenous leuKemia (aml) Unlike ALL and CLL. Among 30. but AML accounts for 15 to 20 percent of childhood leukemia.000 people. 9. Approximately 12. The age of onset is generally later in life. In contrast. The cells affected by this faulty transcription factor are stem cells in either the granulocyte or monocyte lineage.000 people in people between the ages of 65 to 69. incidence increases to 1 in 10. Of 22.040 were AML cases. AML is the result of stem cells in the myeloid lineage becoming cancer cells. The overall survival rate is only 20 percent. a molecule that binds to DNA and regulates gene expression. the malignant state could be shifted to a benign one wherein cells would no longer divide without control. Granulocytes are a type of white blood cell that contain little packets of enzymes to destroy microorganisms.

Prior to this type of therapy. Lance Liotta  Laboratory/National Cancer Institute/U. Differentiation therapy has produced very promising results with acute promyelocytic leukemia (aPl).S. Patients treated with all-trans retinoic acid (ATRA).3  Acute myelocytic leukemia (AML) causes the formation of an  abnormally large number of myelocyte white blood cells. or programmed cell death. National Institutes of Health) cancer cells so that growth can be halted and.Leukemias are not aLL the same 3 Figure 4. cancer cells stop dividing. apoptosis. go into remission immediately. Treatment of APL with ATRA has achieved 80 percent survival after five years. if necessary. a subtype of AML. which is a type of signaling molecule found in embryos. .  (Dr. can be triggered. a retinoid. APL was very deadly.

ChroniC myeloGenous leuKemia (Cml) CML accounts for 15 to 20 percent of all leukemias. or lymphoma can also make a patient more vulnerable to developing AML. Exposure to high doses of radiation. . depending upon dose and duration. ovarian cancer. benzene. fewer than 50 cases per year are diagnosed in the United States. the cause of AML is not understood. which generally occurs only in adults. or even therapeutic radiation. unfortunate side effects of treatments aimed at destroying a primary cancer. effective drugs have been developed that produce very high rates of remission. The specific defect in the stem cell that causes leukemia has been discovered. It is very rare in children. scientists have been able to identify risk factors. however. only 600 died from CML.4 Leukemia As is the case with ALL and CLL. Of 22. Tobacco smoke and chemicals that alter DNA or inhibit the repair of damaged DNA also increase risk. chemotherapy for breast cancer. The median age of diagnosis is approximately 50 years. approximately 4.280 people who died of leukemia in 2006.000 cases are diagnosed per year in the United States. Although the overall survival for CML is a little more than 40 percent. provided the treatment is started early enough in the disease. Among all age groups. This type of leukemia.7 CML has been particularly well studied. Such “collateral damage” resulting in the development of a secondary cancer is one of the potential. the disease progresses very slowly in many cases. increases the likelihood of developing AML. Sadly. represents less than 3 percent of leukemia in individuals between infancy and 19 years. as a consequence.

The chronic phase comes first.  CML has three disease phases. Finally. if any. Few. cells are accumulating more genetic errors and increasing the production of abnormal cells. A person could be in the chronic phase and have no idea that he or she was sick. It can last anywhere from months to years with 3 to 5 years being common. the blast crisis can last from 3 to 6 months. symptoms are evident.Leukemias are not aLL the same 5 Figure 4. Next comes the accelerated phase. During this interval. . which can last 3 to 9 months. or programmed cell  death.4  This diagram shows the stages of apoptosis.

The cells proliferate very rapidly and are resistant to signals telling them to undergo apoptosis and die. Phase 2 of the clinical studies is  done with patients who have the disease or condition to see if treatment is  effective. If all goes well. especially in tumor suppressor genes. the average time is 8. the  drug is approved for marketing in the United States. painstaking. If untreated. They  are monitored for the body’s response to the drug as well as the side effects  that might occur with increasing doses.  synthesis. Leukemia ♦  d ru G develo Pment T he path starting with the research and development of new drugs to  testing  in  humans  and  making  these  new  medicines  available  to  all  patients is a long.  least two species of laboratory animals. Although there is variability in how long it takes from the development of a drug through testing  and appearance on the market. . patients and/or healthy volunteers are given the test drug. Phase 3 expands the drug testing to larger human populations. Next. and does not produce side  effects that outweigh its benefits. During this time.  and  purification  of  the  drug  itself  and  then  an  evaluation  of  its  safety  in  at  monitoring and approving each step of the process.  In all phases of testing from preclinical to clinical. In  Phase 1. and careful one.5 years. The FDA is responsible for  First. the studies are carefully  controlled and subjects are carefully monitored. Every step of the process  and its results are also submitted to the FDA for review. Clinical studies are done in stages. the blast crisis is fatal.  preclinical  research  includes  the  development. clinical studies attempt to  determine whether the drug is safe. is effective. the leukemia cells accumulate even more genetic errors.

. scientists Peter Nowell and David Hungerford. Department of Health and Human Services) The defect observed in 95 percent of CML patients is a structure called the Philadelphia chromosome. The rearrangement of genes caused by this chromosome breakage and rejoining causes cancer because gene function has been altered.  (Stacy Howard/Centers for Disease Control and Prevention/ U. a piece of chromosome 9 breaks off and joins to the broken end of chromosome 22.Leukemias are not aLL the same  Figure 4. all cells derived from it also possess these altered chromosomes. The Philadelphia chromosome.5  This blood smear shows the blast crisis phase of chronic myelogenous leukemia (CML). Specifically.S. is then visibly shortened. this abnormal chromosome is the consequence of chromosome breakage and abnormal rejoining in a stem cell of the myeloid lineage.S. derived from chromosome 22. Discovered in 1960 by the U. Because the event occurs in a stem cell.

In fact.” According to this idea. the resulting fused bcr/abl gene encodes for an abnormal tyrosine kinase. When abl is attached to a site called bcr on chromosome 22. In the case of leukemia. This dysfunctional tyrosine kinase does not communicate properly with the other molecules that turn it on and off. The existence  of relationships between the sites of primary tumors and the secondary  tumors that originate from them suggests that some organs and tissues are  more “welcoming” to metastatic cells. the metastatic cells would grow only  in organs somehow predisposed to forming secondary tumors. it undergoes cell division.” In other words. a type of protein involved in the communication pathway that regulated cell division. and heart. Leukemia Chromosome 9 possesses a gene called abl that encodes for tyrosine kinase. this bcr/abl tyrosine kinase is stuck “on.  When  cancer  cells  break  away  from  a  tumor  and  enter  the  circulatory  system. Cells with tyrosine ♦  t he seed a nd s o il hyPothe s is O nce a tumor metastasizes to other parts of the body. common  metastasis destinations include the brain. spine. Paget’s ideas  . Why might this be so? In 1889. a type of malignant skin cancer. For example. and colon  cancer cells take up residence in the liver. cancer becomes  more  difficult  to  treat  and  the  prognosis  may  be  more  dire.” No matter what signals the cell receives. cancer cells are carried  in all directions when metastasis occurs. the British physician Stephen Paget published a paper in which  he described case histories of cancer patients that led him to propose the  “seed and soil hypothesis.  they tend to make secondary tumors in predictable locations. but they can only grow in tissues  that are “congenial. spreads to lungs.  melanoma.

  Despite  being  correct. but not to dental or medical X-rays. scientists  Ian  Hart  and  Isaiah  Fidler. In fact.S. .  then  secondary  tumors  should be located randomly. researchers are hard at work trying to learn  what it is in a tissue that supports the growth of metastatic cancer cells  and why certain primary tumor cells get preference for this growth. and observing whether or not  secondary tumors form.  were at odds with his professional contemporaries who thought that cancer  cells spread through the lymph and simply lodged in tissues distant from the  original tumor. increases the risk of CML.  Using  clinical  information  about  the  susceptibility  of  certain  organs  to  metastasis  as  well  as  techniques  to  track individual cells to their destinations. Hart and Fidler added more evidence that supports  Paget’s hypothesis.Leukemias are not aLL the same kinase permanently “on” do not stop dividing.  Paget’s  hypothesis  was  not  appreciated in his time. Paget had evidence on his side. The cause of the chromosome breakage that creates the Philadelphia chromosome is not known. It is clear that exposure to high doses of radiation. Other risk factors have not been identified but undoubtedly exist because not everyone who develops CML has been exposed to intense radiation.  The seed and soil hypothesis was resurrected in 1980 by the U. He thought that if metastatic cancer  cells  could  form  tumors  wherever  they  lodged. The cells have become cancerous. They are not. Scientists proposed that the metastatic cells redirected the  new surrounding tissue to become cancerous itself. Paget analyzed 735 case histories and showed that breast cancers spread to the liver more often than  to  any  other  organ.

causes and risk factors. Although there are drugs that can be used as a second line of defense drugs. imatinib can lose its effectiveness as leukemic cells acquire resistance. The chemotherapy drug Gleevec (imatinib) inhibits the abnormal kinase that is made by CML cells. This procedure removes the abnormal stem cells and replaces them with normal ones. .0 Leukemia Because scientists know the molecular genetic and biochemical defect that leads to CML. Under optimal conditions. the only way to actually cure CML is to do a bone marrow transplant. acute myelogenous leukemia (AML). and the likelihood of survival. These leukemias differ in the age of onset. imatinib can produce a 96 percent remission rate. chronic lymphocytic leukemia (CLL). and chronic myelogenous leukemia (CML). Imatinib treatment is most effective when it is initiated early on in the course of the disease. su mma ry Leukemia is not a single disease. there are four major types: acute lymphocytic leukemia (ALL). which then produce normal blood cells. treatment. Eventually. In fact. efforts to design effective drugs have been very successful.

♦ The cause(s) of childhood leukemia are not known. ♦ Tremendous progress has been made in treating childhood leukemia successfully. ♦ ♦ ♦ Leukemia in children is almost always acute. Infant leukemia is a subset of childhood leukemia.ChILdhood LeukemIa 5 Key Po ints ♦ Leukemia accounts for approximately 25 percent of all childhood cancers. and high energy radiation. 1 . Two hypotheses are exposure to pesticides. ♦ Some of the treatments can produce long-term side effects including secondary cancers. not chronic. The symptoms of childhood cancer are similar to those seen in adults.

and favorite doll Molly. brother. Jennifer’s doctor ran some blood tests and on December 24. Jennifer had to endure some terrible side effects brought on by her chemotherapy. On Thanksgiving Day 1993. She had a sore throat. They wanted their daughter to survive but did not wish for her to suffer any more. Jennifer’s family noticed that she was tiring easily and running a low-grade fever. Jennifer’s parents also turned . They decided to forego another round of chemotherapy and instead opted to have physicians try a bone marrow transplant. happy 5-year-old girl who lived in Dallas. Her parents were not immediately worried but when Jennifer did not improve and her parents realized that she was bruising very easily. they decided to have her examined by their doctor. Three rounds of treatment were planned. Jennifer’s condition was critical. Jennifer’s parents had some difficult choices to make. They did a procedure called leukapheresis. Even worse. Texas. Jennifer began chemotherapy right away. 1993. developed skin rashes. and Jennifer’s family and medical caregivers were delighted when she went into remission after only two rounds. her leukemia came roaring back by April 29. Additional tests confirmed this diagnosis. father. She also had more than the “usual” number of bruises expected on a 5-year-old. which filters the blood to reduce the number of abnormal leukocytes.2 Leukemia Jennifer Stroud was a normal. Physicians prescribed other drugs to help reduce these side effects and Jennifer recovered enough to come home. with her mother. Unfortunately. She lost her hair and her appetite. Jennifer was admitted into the hospital because the preliminary tests suggested that she had leukemia. Physicians initiated emergency treatment. Jennifer’s parents learned that their daughter had AML. and bruised even more easily and deeply. Jennifer’s eyes dehydrated so much that she could not see and she had fevers spike to 106oF. Sadly. 1994. the evening of that same day.

As hard as Jennifer and her family fought. 1995. but had to be isolated from people until she had enough healthy leukocytes in her body to fight off infections.ChiLdhood Leukemia their energies toward identifying nutritional and other types of treatments to lessen side effects and improve their daughter’s quality of life. Jennifer died February 1. they agreed and combined this new chemotherapy with specific nutritional approaches. Jennifer’s condition was stable throughout almost all of 1995 but her leukemia returned once more. If the molecules on the cell membranes of the donor and recipient are very different. and that the only remaining option was to try an experimental drug. The Strouds tried the next option. Bone marrow transplantation requires a close biochemical match between the cells of the donor and those of the person receiving the transplant. Jennifer’s bone marrow transplant was performed in September 1994. Unfortunately for Jennifer. On February 2. The physicians told Jennifer’s parents that she would survive no longer than another month. Unwilling to let any possibility go untried. She was eight years old. The usual procedure for identifying a good donor is to test close relatives. Jennifer was physically weak but her parents did everything they could to strengthen her through nutrition and other remedies. they searched for a donor through the National Marrow Donor Program. As Jennifer’s energy and stamina improved. neither of her parents nor any close relative was a suitable match. this battle was not going to be won. 1996. The transplanted cells will not survive. The bone marrow transplant did not cure her. She also wrote to other sick children to encourage and help them. the recipient’s body will “reject” the transplant. Jennifer’s leukemia was back.2 3 . Nothing more could be done. she was sometimes able to attend school and play with her friends.1. She returned home in October 1994. This effort was more successful—they identified a donor in Canada.

It accounts for approximately 25 percent of all childhood cancers. For example. This metastasis can result in severe headaches. leukocyte counts are already very high and leukemia has often spread to the brain and spinal cord by the time of diagnosis in infant leukemia. They tire easily. leukemic cells metastasize or spread to the brain and spinal cord.4 Leukemia tyPes of leuKemia in Children Leukemia is the most common type of cancer occurring in children. problems with balance. CML is very rare in children. and 6 percent with ALL. In 12 percent of children with AML. Roughly 60 to 75 percent of leukemias are ALL. seizures. and are susceptible to infection. cases of infant leukemia arise in utero. and altered vision. is another subset of childhood leukemia. if not all. bruise and bleed more. fewer than 50 cases are diagnosed each year in the United States. It appears likely that most. Children with leukemia experience the same range of symptoms as those seen in adults.4. Approximately 2. Sometimes ALL can spread to the lymph nodes inside the . not chronic. and 2 to 5 percent are CML. 25 to 38 percent are AML. leukemia appearing in infancy is slightly more predominant in females. The biology of the disease in infants is different from what is seen with older children. get frequent nosebleeds. whereas in older children it is more likely to occur in males. Also. most leukemias in children originate from the lymphoid lineage. Scientists hypothesize that infant leukemia originates from a stem cell that did not fully commit to normal development and differentiation. Interestingly.3. Leukemias in children are almost always acute.200 children are affected each year in the United States alone. Leukemic children also lose their appetites and may experience bone pain and nausea.5 Infant leukemia. before a baby is born. whereas in adults 85 percent of leukemias are myeloid. which is diagnosed within the first 12 months of life.

ChiLdhood Leukemia 5 Figure 5.S.1  This young girl is receiving chemotherapy for  acute  lymphocytic leukemia (ALL).  (Bill Branson/National Cancer Institute/U. National Institutes of Health) . The majority of childhood leukemias  are ALL.

Leukemia in identical twins apparently starts in utero. leuKemia in twins The first published description of identical twins who both developed leukemia was in 1882. This metastasis to the chest lymph nodes can also interfere with blood vessels. or windpipe. even nonidentical twins. and the siblings of leukemic children have less than a 2 percent incidence of developing the disease by the end of their teens. thus impeding the flow of blood to and from the heart. A stem cell becomes leukemic in one twin. children face less than a 1 percent chance of developing leukemia by age 20.6 More specifically. . Scientists have shown that identical twins share a single bloodstream and placenta. Generally parents first notice that their child is tiring more easily and seems “not right. and then when it undergoes repeated cell divisions. the structure in the mother that delivers oxygen and food molecules through a network of blood vessels. some of the newly produced cancer cells spread to the other twin through the placenta. If one identical twin develops leukemia before 6 years of age. the trachea. which connects both of their circulatory systems. siblings of childhood leukemia patients. Since then approximately 70 cases have been reported. Leukemia chest. the other twin has a 20 to 25 percent chance of developing ALL or AML.” A trip to the pediatrician and a physical exam might reveal swollen lymph nodes and/or a swollen spleen. In contrast. When this event occurs. diaGnosis of Childhood leuKemia Determining whether a child has leukemia uses similar methods to those needed to diagnose an adult. have only twice the low level of risk faced by all children. can become “crowded” so breathing becomes impaired.

As with most cancers. Finally. a procedure by which a doctor inserts a needle into the spinal column. treatments. The pathologist examines the spinal fluid to see whether any cancer cells are present. scientists are not exactly sure about what causes the disease. is so powerful that fund-raising for leukemia research has been very successful. Similarly. Similarly. the doctor would next take a sample of bone marrow and a pathologist. or examined for the presence of cancer cells. These efforts are bearing fruit because scientists have learned more about risk factors associated with childhood leukemia than they know about adult forms of the disease. whether they are there in adequate numbers. the child’s lymph nodes would also be biopsied. and collects spinal fluid. and scientists who have devoted their lives to figuring out causes. research interest is intense. Childhood leukemia cannot be attributed to one specific risk factor. and there are many families. a medical scientist who studies disease. The vision of babies and young children suffering from leukemia. the potential causes are cumulative and people . The physician would run blood tests to see what kinds of cells are present. physicians. If appropriate. a resource funded by the United States government. a child suspected of having leukemia might also undergo a lumbar puncture.ChiLdhood Leukemia evident by feeling the left side of the abdomen. provides competitive grants for scientists studying leukemia and other diseases. or any cancer for that matter. and if any abnormal cells are observed.  what Causes Childhood leuKemia? As is true for all forms of leukemia. and prevention. Leukemia in children packs an understandably emotional punch. the National Institutes of Health (NIH). would evaluate whether abnormal stem cells and leukemic cells were present. In the case of childhood leukemia.

8. Scientists think this relationship strengthens the hypothesis about the association between exposure to infection during the first year of life and the development of leukemia. during the first year of life increases the risk for leukemias. than in poor. Their idea is that children in affluent. other studies have shown that the absence of exposure to common infections. In both cases. childhood leukemia is more prevalent in socioeconomically advanced. not just ear infections. and ALL specifically. and chance.10 In fact. Similarly. including the abnormal proliferation of poorly developed leukocytes. Alternatively. valuable because it can help with prevention.7. For example. For example. Many scientists hypothesize that childhood leukemia may be related to the inadequate development of an infant’s immune system.” Obviously they are not arguing that babies or young children . developed countries. some scientists suggest that affluent parents are overly concerned with hygiene and keep their children “too clean. the disease may originate because an infant was not exposed to the common infections that occur in early childhood.9. exposure to common infections later might trigger a dysfunctional immune response. developing nations. studies have revealed that children who have had ear infections in early childhood have a reduced risk of leukemia. Information about risk factors is. however. Some observations support this hypothesis. their innate susceptibility probably due in part to their genes. Interestingly. developed countries are generally more isolated from crowds of people and from “dirt” than are children in developing countries. It is likely that any individual children who develop leukemia do so because of their own particular exposures to risk. Leukemia vary in their susceptibilities. United Kingdom. the incidence of ALL in children between the ages of 2 and 5 years is 10 times higher in the United States. and Japan than it is in Africa.

Although scientists tried to identify possible causes including exposure to chemical pollution. a previously isolated population exposed to a new microbe resulted in illness among susceptible individuals. Given that childhood leukemia can develop so early.000 years.11 As happened when Europeans first came to North America. Scientists speculate that this large “foreign” population brought with it new microbes to which the children of Fallon had never been exposed.000 people from outside the area. there have been observations of disease patterns that support this notion. Between 1997 and 2002. they ultimately hypothesized that the Fallon “cancer cluster” resulted from a local epidemic that was triggered by the mixing of a large population into their relatively small rural one. The entire population of Fallon was only around 7. This town experienced an unusually high incidence of childhood leukemia. who entered the town for nearby military operations. Scientists who studied the incidence of leukemia in this population concluded that this number of cases occurring randomly and without direct cause was an event of such low probability that one would expect to see it once every 22. there were 16 cases in all: Three of these children died. and 15 out of the 16 cases were ALL. One example of such a pattern occurred in Fallon. Although no specific virus or bacterium has been identified. initiating even before birth. Nevada. Another tantalizing idea about childhood leukemia is that there are cases that are actually caused by an infection in susceptible individuals.ChiLdhood Leukemia should be neglected. scientists realized that it made sense to examine the effects of maternal exposure to risk factors and the development  . Experts suggest that the origin of this particular epidemic was the arrival of 100.500. but they wonder whether well-intentioned parents have gone too far in protecting their offspring from exposure to the natural messiness of ordinary life.

0 Leukemia ♦  C u r Cumin: wo nder d ruG ? in the search for additional treatments.  the  incidence  of  childhood leukemia is lower in Asia compared to other places in the world.  Is there a relationship between turmeric and cancer prevention? Scientists have focused their attentions on curcumin. Studies showed that pregnant women who supplemented their diets with folate decreased the risk of leukemia in their children. I n  addition  to  the  development  of  new  drugs  to  fight  diseases  like     leukemia. scientists are also looking to ancient remedies and nutrition  of leukemia in children.  More  experiments in mice demonstrated that curcumin restored the population  of  immune  cells  that  fight  cancer  cells. Turmeric is also  a  common  ingredient  in  Asian  cooking. experiments . slows the process called angiogenesis in which blood vessels grow to connect tumors to the circulatory system. and stops  inflammation. Experiments have shown that  curcumin can prevent human leukemia cells from multiplying in culture. the compound  in turmeric that gives it a vivid yellow color.  Other experiments revealed that curcumin was able to induce apoptosis.  or  cell  death. Maternal diet was influential. triggers apoptosis in several types of cancer cells. Similarly. The spice turmeric has been used  for thousands of years in Ayurvedic medicine from India.  in  two  different  types  of  leukemia  cells  in  culture.  And  yet  more  experimentation  has shown that curcumin slows metastasis. The preclinical findings have been so positive that human  trials are under way to see whether curcumin can be developed as an effective weapon in the arsenal to fight cancer.  Interestingly.

on the other hand. A healthy. Therefore any chemical that causes DNA damage or permits it to go uncorrected will increase the risk of cancer. soybeans. helps prevent DNA breaks and the consequent damage. Folate. 1 . In contrast. are fundamentally genetic diseases in that they develop from damaged or mutated genes that lose the capacity to regulate cell division. Why would maternal folate consumption decrease leukemia risk whereas eating too many bioflavinoid-containing foods increase it? The answer resides in understanding what each of these types of molecules does to DNA. any chemical that prevents DNA damage or helps with repair will decrease the risk of cancer. cocoa. including leukemia. increased the risk of infant leukemia.ChiLdhood Leukemia with rodents demonstrated that a diet in which calories were somewhat restricted. protected against the development of leukemia induced by radiation or chemical exposure. including treatment for other types of cancer. which is essential for DNA repair. Exposure of children to several physical and chemical factors also increase leukemia incidence. pregnant women who ingested high amounts of bioflavinoids such as fruits and vegetables that contain quercetin. balanced diet and not focus on any single food. topoisomerese ii. wine. Examples of possible risk factors include exposure to high doses of radiation. In contrast. and fruits and vegetables are a critical component. balanced diet during pregnancy is essential. particularly AML. chemotherapy for other cancers. exposure to these factors in utero increases the risk of leukemia even more. In many cases. In the specific case of leukemia. and caffeine. tea.12 This finding should not be overinterpreted. bioflavinoids increase risk because they can cause a break in DNA molecules and inhibit an enzyme. All cancers. It is important to eat a varied. and that contained both the spice curcumin and the oil geraniol.

  was  working  as  a    pathologist in Boston. at Children’s Hospital in the  . In the mid-1940s. and the will to persist. In fact.D. the prognosis for patients with leukemia was grim.D. Both of these diseases involve the production of an excess of  immature blood cells that crowd the bone marrow. Could a treatment be  developed that would stop the production of abnormal bone marrow in  leukemic patients? W hen  Sidney  Farber.2 Leukemia sPot liG ht o n CanCer sCie n t is t s : s i D n ey a.  Farber  was  intensely  driven  to  cure  cancer.  an  American  physician. f a r B e r. adequate resources. Farber  earned  his  M. it  had  not  really  changed  appreciably  since  the  1840s  when  leukemia  was  first  described.  Farber  thought  a  similar  treatment might work with leukemia.  His  clinical  experiences working with young patients at Children’s Hospital may have  provided  the  spark  that  caused  him  to  devote  his  life  to  curing  childhood cancer. Scientists discovered  that treatment with vitamin B12 could cure pernicious anemia and that  folic  acid  was  successful  against  tropical  anemia. Massachusetts. M .  Because  leukemia  is  also  a  problem  with  bone  marrow  function. Farber considered research that had been  conducted during World War II to treat pernicious anemia and tropical anemia. Born in 1903 in Buffalo. (1903– 1973) mid-1940s.  from  Harvard  Medical  School  in  1927. He knew that folic acid stimulates  bone  marrow  growth  and  wondered  what  would  happen  if  he  blocked  the normal action of folic acid found in the body. the third of 14 children.  He  reasoned  that science could succeed in this endeavor with creative and energetic  research. New York.

National Institutes of Health) . a type of kidney cancer that occurs in  children. had more than tripled to $167 million  by 1967.2  Dr.S. Starting in the 1950s and continuing until his death in 1973.  Since  this  first  demonstration  of  remission  of  any  leukemia.  many  other  scientists  have  advanced  chemotherapeutic treatments  not only for ALL.  on  16  children  with  ALL.  Farber acted as a “medical diplomat. but for other  leukemias as well.  most  notably  the  discovery  that  treatment  with  actinomycin  D  and  radiation  would  produce remission in Wilms’ tumor.13 Figure 5. Sidney Farber.  10  of the children had temporary  remissions. only $48 million in 1957.  (National Library of Medicine/U.” regularly presenting information  at congressional hearings to increase federal support for cancer research.ChiLdhood Leukemia 3 In  late  1947.  He was successful in this task: The annual budget of the National Cancer  Institute.  To  his  delight.  Farber  tested  aminopterin. Farber  made  additional  research  breakthroughs  in  the  1950s  and  1960s.  a  molecule with a structure similar  to  folic  acid.

and exposure to pesticides. Exposure to pesticides from professional extermination is most dangerous during the ages of 12 to 24 months.4 Leukemia immunosuppressive drugs taken after organ transplantation. the use of pest strips indoors is strongly associated with leukemia. treatment The vigorous research effort on childhood leukemia has also yielded wonderfully effective treatments. certain other diseases such as Down syndrome. studies of the unfortunate nuclear reactor accident at Chernobyl have not revealed any relationship between exposure to low levels of radiation and development of infant leukemia. li-fraumeni syndrome. Scientists have also determined that children are more likely to develop leukemia after pesticide exposure if they are very young. remission rates exceed 90 percent and the majority of children remain permanently in this state. Scientists have also examined other potential risks that so far have not yielded any clear association with childhood leukemia. only 25 percent did so. by 2000. and fanconi’s anemia to mention three examples. Whereas nearly 100 percent of children with leukemia died in 1950. In particular. and fetuses are at increased risk in utero. Today. Similarly. For example. The association between pesticides and childhood leukemia has been especially well studied. no studies have found evidence for an association between proximity to electrical installations or to magnetic fields and leukemia incidence. . probably because this risk factor could be eliminated. Scientists have demonstrated that exposure to pesticides indoors is more dangerous than outdoors.

The specific tools or methods used for treatment are chemotherapy. Fortunately. with ALL. For example. Many cancer treatments produce undesirable side effects. induction therapy. in which lower doses of treatments are given to kill any remaining leukemia cells. ALL survivors are much shorter than 95 percent of children their age. The second phase is called consolidation or intensification therapy. is designed to kill the leukemia cells in the blood and bone marrow. and stem cell transplantation. As a consequence.ChiLdhood Leukemia The specific treatment plan designed by physicians depends upon the specific type of leukemia and how serious the disease is at the time of diagnosis. For instance. nausea. In fact. The goal of this first phase is to induce remission. radiation therapy. The first. curing ALL in children can negatively impact their physical and intellectual development. and vomiting. There can also be long-term health consequences due to treatment. With radiation therapy. short-term side effects of chemotherapy include hair loss. The objective here is to kill any remaining leukemia cells that are not dividing but might do so in the future. The third phase is maintenance therapy. recent studies have shown that childhood survivors of ALL can be treated safely with growth hormones in order to regain height. treatment for ALL inhibits production of growth hormone. there are three phases of treatment. 5 . high-energy X-rays are used to kill cancer cells. For example. In most cases these treatments would be used in combination. Consolidation therapy is done to prevent a relapse or recurrence of leukemia. Radiation therapy makes a patient extremely fatigued after treatments. Chemotherapy refers to the administration of drugs designed to kill cancer cells. Stem cell transplantations are done when it is necessary to replace the normal stem cells if they are destroyed by chemotherapy or radiation.

Scientists studied the incidence of secondary cancers in 2.290 patients who remained in complete remission. Third. Consequently. there is a population of survivors who have lived for decades after treatment. Other types of cancers that developed included myeloma. carcinoma. The majority of children have permanent remission. Leukemia The most serious potential side effect from the treatment of childhood leukemia is the development of secondary cancers. an epithelial cell cancer. it is possible to trigger cell death by therapeutic means. Second. unlike cancer cells that develop in . At this early stage of development. Scientists have formulated several related hypotheses to explain this difference. a tumor of connective tissue. the leukemic cells can spread or metastasize in the fetus without having to bypass these normal controls. and basal cell carcinoma. First.169 children and adolescents who had been treated for ALL between 1962 and 1998. because the leukemic cells in a young child never bypassed the apoptosis control. The treatment of childhood leukemia is one of the greatest medical success stories of the twentieth century. a type of bone marrow cancer.14 The most common forms of these cancers were meningioma. Because ALL is one of the most curable forms of childhood cancer. many if not most childhood leukemias originate in the fetus. Of the 1. brain tumors. The risk to ALL survivors for secondary cancers far exceeds the cancer risk of the general population. Therefore the cancer cells are not as abnormal as they would be in adults at the same stage of the disease. a tumor of epithelial tissue. and sarcoma. which affects the lymph nodes. 95 percent developed a secondary cancer. lymphoma. a tumor near the brain and spinal cord. It is interesting to wonder what it is about childhood leukemias that make them more responsive to treatment than the adult forms of the disease. the normal cellular controls of cell proliferation and apoptosis are not fully in place.

brain. leukemic cells in young children do not display too much genetic instability or altered genes. In 1950. has improved dramatically in recent years. The risk factors and causes of childhood leukemia are not understood fully although scientists are exploring many hypotheses.  su mma ry Leukemia. particularly ALL. Because adult cancers result from the accumulation of many genetic mutations. bruising. some of the treatments can produce undesirable side effects such as secondary tumors. the most common form of cancer in children. The treatment of childhood cancer. swollen spleen. metastasis of leukemic cells can produce tumors around the spinal cord. they can be very difficult to treat. leukemic cells in children have little opportunity to develop resistance to treatment. almost all children with leukemia died. throughout childhood. . and other sites in the body. and in adolescence. Unlike the situation in childhood leukemias. whereas remission rates are now greater than 90 percent. Unfortunately. The symptoms of leukemia in young patients are similar to those experienced by adults: fatigue. Finally. can occur in patients at birth. adult cancer cells have bypassed cell proliferation and apoptosis controls.ChiLdhood Leukemia adults later in life. and bleeding. because they develop more quickly than adult cancers. infections. In addition.

and the Soviet Union were united in their battle against the spread  . ♦ Exposure to benzene and certain other chemicals is clearly linked to the development of leukemia.externaL rIsk faCtors and Causes of LeukemIa 6 Key P o ints ♦ Exposure to high energy radiation is associated with cancer. lessons from hiroshima The United States officially entered World War II in December 1941 after Japan bombed Pearl Harbor. Adult T-cell leukemia is caused by infection with the human thymusderived T-cell leukemia virus (HTLV-1). leukemia in particular. ♦ ♦ Exposure to herbicides and/or pesticides increases leukemia risk. The United States. Great Britain.

the United States had been involved in the Manhattan Project. fighting with Japan continued on the Pacific front. A firebomb raid in March 1945 had killed almost 100.000 Americans. In 1945. the United States became the only nation to have used a nuclear weapon in war when a B-29 bomber called the Enola Gay  . Historians disagree about whether Truman made the right choice.externaL risk FaCtors and Causes oF Leukemia and domination of Nazism and Fascism in Europe even as the United States and Great Britain fought a second front in the Pacific against the Japanese. Unbeknownst to the Japanese. a secret effort to develop an atomic bomb. Nevertheless. high-casualty ground force invasion. and approximately 100. Unfortunately. If such an invasion was to be undertaken. In addition. On August 6. the predicted death toll from an invasion of Japan was ghastly. Germany surrendered unconditionally. The initial landings of troops were scheduled for the fall and winter of 1945–1946. thus ending the long European conflict. military experts generally agreed that the Japanese would never surrender and that ground invasion of the island was going to be necessary to end the war.000 military aircraft.S. 100. President Harry Truman made the controversial decision to drop an atomic bomb on Japan with the objective of getting Japan to surrender without the need for a protracted.000 native Okinawans. Japan gave no signs of being willing to surrender even though U. Given that the campaign to capture the island of Okinawa took more than 10 weeks and resulted in the deaths of more than 12. it was certain to be costly in terms of lives lost and people injured.000 Japanese. 1945. the United States Navy had successfully cut off all supply deliveries to Japan.000 people and injured more than one million in Tokyo. This city was bombed again in May 1945 and another 83.000 people were killed. There were two million Japanese soldiers in Japan and they had approximately 10. aircraft were bombing cities in Japan.

This exposure to radiation increased the incidence of cancer.000 soldiers present.) At the time.000.0 Leukemia dropped a 9.4 square miles of the city. At least 70. Almost all structures within a mile of the bomb were destroyed and buildings within 3 miles were badly damaged. the population of Hiroshima was approximately 300.900 feet above the city with a force equivalent to 15. The consequences of the bomb were devastating. especially leukemia. Terrible fires engulfed the city. (This was followed on August 9 by the atomic bombing of Nagasaki. 1945. in populations in and near Hiroshima. By 1950. 90 percent of people within a half-mile radius of the bomb’s center were dead.700-pound uranium bomb on the city of Hiroshima. The bomb was dropped and it detonated 1.000. but one of the worst long-term effects of the bomb was radiation fallout or contamination. Japan surrendered on August 15. the death toll exceeded 200. The bombings of Hiroshima and Nagasaki may have ended the war but they also initiated a huge unintended experiment that asked: What happens to a large population of people in the years following exposure to massive levels of radiation? The Hiroshima population received medical help and was monitored very shortly after the blast.000 because of aftereffects such as radiation sickness.1. By the end of 1945. reported that X-rays were carcinogenic. In 1902 Albert Frieben. Within minutes. Flames destroyed more than 4. The entire exposed population .2 exPosure The association between cancer and radiation was well known long before World War II.000 people died from the initial blast.000 tons of dynamite. a German scientist. the death toll exceeded 100. The city was a military center and there were about 43.

In addition to the observations of the relationship between radiation and leukemia revealed by the Hiroshima population. Moreover. which is caused by chromosome breakage and the creation of the Philadelphia chromosome. The relationship was linear. Therapeutic X-rays to the thyroid region in childhood or in utero exposure also increases leukemia incidence. 1 . radiologists who performed X-ray examinations of patients and people working with radioactive materials in an industrial setting were particularly vulnerable. a genetic change associated with the occurrence of CML. the greater the incidence of leukemia. to develop after the damage so it is no surprise that leukemia incidence continued to rise even years after the bomb. Scientists also evaluated the outcomes of exposure to various levels of radiation and found that the higher the radiation dose. For example. The relative leukemia incidence diminished but was still higher than that of the general population 13 years after the bomb. occupational exposure to high-energy radiation also increased leukemia incidence. It can take a while for leukemia. the peak incidence occurred from 1950 to 1952. A paper summarizing the observations of survivors from 1945 to 1958 reported a higher incidence of leukemia among people closest to the epicenter.externaL risk FaCtors and Causes oF Leukemia was also monitored every two years thereafter. This higher incidence was evident more than three years after exposure.3 Radiation is believed to increase the likelihood of developing leukemia because it damages DNA and chromosomes. or any cancer. Scientists also observed that the most prevalent type of leukemia in atomic bomb survivors was CML. Similarly. scientists have also demonstrated that exposure to radiation therapy for other cancers increases the likelihood of developing leukemia. in the days before adequate safety measures were taken to protect workers.

”  Radiation  therapy  continues to be an essential tool for the treatment of many forms of cancer.2 Leukemia sPot liG ht o n CanCer sCie n t is t s : M a r i e c u r i e (1867–1934) Although  it  is  true  that  she  did  not  study  medicine  or  biology  directly. Marie worked as a governess and helped finance her sister’s  medical  studies.  Marie  Sklodowska  was  the  youngest  of  five  children in a relatively poor family.  This  procedure  was  called  “curie-therapy. Marie attended Sorbonne University  and  studied  physics  and  math.  she  met  Pierre  Curie. Marie Curie.  Marie Curie is not a name generally associated with cancer research.  In  1891. and continued their personal  and professional collaboration until his death in 1906.  another  scientist.  When World War I erupted in 1914.  one  for  Chemistry  and  one  for  Physics.  it  was  Marie’s  turn. Marie Curie reasoned.  Marie Curie also realized that X-rays could be used to see inside the body. her  mother died and her father was not able to support her financially. Born  in  Poland  in  1867. While still a very young woman. Driven to learn. in 1895. along with her 17-year-old  daughter  Irene.  In  1894. As a  consequence. correctly. and helping make surgeries  W inner  of  two  Nobel  Prizes. detection. and treatment.  Curie’s discovery of the radioactive element radium and her development  of  its  applications  provided  important  information  about  cancer  causation.  locating bomb shrapnel or bullets in bodies.  .  One of the earliest medical uses of radiation was to treat malignancies.  She  moved  to  Paris  and  lived with her sister. They married a year later.  equipped  ambulances  with  X-ray  units  and  traveled  to  where injured soldiers were located. that  X-ray examination would be a critical help for visualizing broken bones.

 she died of leukemia in  1934.  also a Nobel Prize–winning physicist.    ( AP Images) more  accurate. Marie  Curie demonstrated this relationship personally. The family sacrifice did not end there. . died of leukemia in 1956.externaL risk FaCtors and Causes oF Leukemia 3 Figure 6. High-energy radiation is associated  with an increased risk of certain cancers.  Irene’s  death  has  been  attributed  to  excessive  radiation  exposure. Eventually. As is true  of  her  mother. Sadly. Marie Curie’s daughter Irene.  This  pioneering  use  of  X-rays  has  been  extended  to  the  many types of visualization techniques that modern physicians have to see  tumors inside the body.1  Marie Curie (seated) with her daughter Irène Joliot-Curie. such as leukemia. the long-term exposure to radioactivity revealed one more important fact.

exposure to benzene was the only commonality. and metal engraving. two Italian physicians.4 Lignac was able to show experimentally what had been suspected from retroactive studies of people: Benzene dramatically increased the likelihood of leukemia. In 1928 Delore and Borgomano. public health professionals. Because benzene was used liberally in manufacturing. At the end of the experiment. In 1932 Dr. Such is the case for the chemicals associated with increased risk of leukemia. did an experiment in which he administered 0. maybe even years. exposure was a serious problem affecting many workers in the early twentieth century. or any cancer.001 milliliters of benzene dissolved in olive oil to 54 white mice. none of these animals developed leukemia. is tightly linked to the development of leukemia. physicians. especially benzene. He fed the benzene to the mice weekly for between 17 and 21 weeks. a French scientist. Lignac. Lignac also had 1. a different type of blood cancer. For the people working in this wide range of industries.465 control mice to which no benzene had been given. or scientists notice an increase in disease incidence in those who were exposed. were the first to report a case of “benzene leukemia” in a person who had been regularly exposed to that chemical in his work.4 Leukemia ChemiCal exPosure Information about possible risk factors or causes of leukemia. and they developed leukemia at rates much higher than the . Lignac observed that 6 of the 54 mice had developed leukemia and 2 more had developed lymphoma. Benzene Exposure to industrial solvents. often come from an unintended “experiment” wherein a population of people is exposed to some material and then some time later. leather working.

. as is true for most carcinogens. the lag is anywhere from 3 years to more than 20 years. and because leukemia is caused by an accumulation of errors in DNA. With benzene and leukemia. the phenoxy herbicides. who worked from 1959 to 1966 in a beauty case factory.externaL risk FaCtors and Causes oF Leukemia general population. a 37-year-old woman. the most vulnerable individuals are children. as with radiation. The increased leukemia risk in those exposed is not dramatically higher than that of the general population—no more than approximately 1. the time it takes after exposure for the damage to occur influences how quickly a person develops leukemia. assembled the case by spreading the benzene-containing glue with her finger over the lining of the case. a 36-year-old woman working from 1942 to 1964 as a finisher of electric cables. had to shape the toes of the shoes by softening the leather with 40 percent benzene. Nevertheless. a 31-year-old man. However. For example. Workers exposed to benzene often exhibit chromosomal damage. concern about these environmental chemicals is intense because. For example.5 times greater. are linked to CLL. there can be a time lag of years between exposure and the onset of the disease. She also died of leukemia in 1967. 5 Pesticides and herbicides The other principal categories of chemicals associated with leukemia are herbicides and pesticides. who worked as a shoemaker from 1959 to 1961. In a third case. used to kill leaf weeds. The majority of more than 30 studies in the medical literature show an association between adult leukemias and farming and/or herbicide/pesticide exposure. used benzene to clear the rubber covering for the wires and died of leukemia in 1967. He died of leukemia in 1965. Similarly.5 It is clear that the association between benzene exposure and leukemia development is a strong one.

 Leukemia Figure 6.2  Benzene was once a common chemical used in making  leather items. such as shoes.  ( http://www. Exposure to benzene can cause  chromosomal damage that can cause a cancer such as leukemia to  form.it /Alamy) .vittorebuzzi.

After all. Ironically. probably by damaging the blood stem cells of the bone marrow. Rous was vindicated. a chemical that is sometimes used as a preservative.externaL risk FaCtors and Causes oF Leukemia Besides benzene. chemicals that alter DNA structure. are caused by infection was a long and tortuous one. The scientific community did not think that this discovery was particularly important. Other cancer . For example. Eventually. The rous sarcoma virus (rSV) was the first of many tumor viruses that scientists discovered. Finally. the next big breakthrough was another observation made in chicken. a muscle tumor. Volatile solvents are chemicals that evaporate into a gaseous form at room temperature. chickens are not at all like humans. scientists and physicians did not fully understand that leukemia was a blood cancer. In 1908 the Danish scientists Vilhelm Ellerman and Oluf Bang showed that a virus caused chicken leukemia. the reasoning went. so this finding is irrelevant. formaldehyde. Also. the scientific community was underwhelmed by this amazing finding. pesticides. Because solid tumors do not form in leukemia. scientists believe that exposure to certain other volatile solvents that damage bone marrow increases the risk of leukemia. and tobacco smoke all increase the risk of leukemia. and herbicides.  infeCtion The experimental and intellectual path to the understanding that some cancers. In 1911 the American scientist Peyton Rous demonstrated that sarcoma. chemotherapy drugs used to treat other cancers. Again. is associated with leukemia. in 1908. chemicals that prevent DNA repair. this disease did not resemble the cancers with which physicians were more familiar. including a certain type of leukemia. was caused by a virus.

 Fibiger  learned that the cockroach was the intermediate host for the worm. Armed  with this knowledge. he infected cockroaches with S. The Shope papilloma virus was shown to produce large skin tumors. and he was awarded the Nobel Prize for Medicine or Physiology in 1966. This factor is the Bittner virus. In fact. in the 1930s. especially by tumor-causing viruses? First. Similarly. between 1951 sPot liG ht o n Ca nCer s Cie n t is t s : J o h a n n e s f i B i g e r (1867– 1928) W inner of the Nobel Prize for Physiology or Medicine in 1926. a nematode worm was present in the gut too. Johannes  Fibiger’s  work  is  barely  described  in  the  information  disseminated  about him by the Nobel Foundation. Of 62 rats that survived for more  . two oncogenic. Although leukemia was recognized as a cancer during the late nineteenth century. or stom- is because his Nobel Prize–winning discovery could never be replicated by  ach. viruses were observed in mammals. carcinoma and fed  the infected insects to laboratory rats. Fibiger observed that in three cases of spontaneous gastric. Perhaps the reason for this reticence  other scientists. cancer in wild rats. it was not until 1951 that Ludwik Gross showed leukemia in mice was caused by a virus. or cancer-causing. Leukemia researchers finally caught up with Rous. especially on the head. He  named this worm Spiroptera carcinoma and studied its life cycle. What other pieces of evidence needed to be put in place for scientists to accept the hypothesis that some cancers are caused by infection. John Bittner discovered a factor present in mouse milk that can cause mammary tumors.

 the scientific community ignored these results for a long time probably because  the  idea  of  an  infectious  cause  for  cancer  had  been  so  embarrassingly  discredited. carcinoma  caused stomach cancer. Evidently. . Fibiger concluded that S. adult T-cell leukemia. Fibiger  died  in  1928  shortly  before  other  scientists  demonstrated  that  the  rats  had developed cancers because of a lack of nutrition. Given that more than 15 percent of cancers worldwide are probably due to infection. It is particularly ironic that Fibiger’s  Nobel Prize in 1926 was the first one awarded in the field of the infectious  causes of cancer.externaL risk FaCtors and Causes oF Leukemia and 1972. In 1975 David Baltimore was awarded the Nobel Prize for demonstrating that tumor viruses physically interact with the cell’s genes. the worms  played no part in the story after all. In the case of leukemia. When evidence did emerge that some cancers are indeed  caused by infectious agents. viruses produce cancer by damaging or altering DNA structure and/or function. 12 developed stomach cancer. is caused by human thymus-derived T-cell leukemia virus (HTLV-1). Finally scientists could see that these infections were caused by discrete particles that had a physical basis. one particular form.  than 60 days. As with radiation. no one could duplicate these findings. Interestingly. He published this work in 1913. 26 mammalian oncogenic viruses could be visualized using an electron microscope. Despite many efforts. it is startling that it took so long for the scientific community to accept this reality. the worms and  their eggs were present in the primary tumors but not on the secondary  tumors that resulted from metastasis. especially certain types of viruses.

 The disease spreads when fluids. feline leukemia is caused  .  The  best  approach  is  prevention  by  vaccination  and  keeping cats indoors and away from infected cats. the viral RNA enters the cell and takes over its biochemical machinery. approximately 2 to 3 percent  of all cats are infected.  Kittens  are  much  more  susceptible  to  infections  than  are  adult  cats. water or food bowls. such as saliva. Because the immune system is severely weakened. Although FeLV does not infect humans.  people  should  avoid exposure to infected cats. retroviruses use RNA. cats can  too. Some cats with feline  leukemia develop solid tumors and severe anemia. Approximately 20 percent  of infected cats will die. Feline leukemia is a potentially fatal disease. Instead of containing DNA as their genetic material.100 Leukemia HTLV-1 is an example of a retrovirus. and bedding in addition to cat-to-cat contact.  affected cats are likely to suffer from infections. Treatments are aimed at relieving  pain  and  suffering. There is no cure for feline leukemia.  pass  from  an  infected  cat  to  another  cat.  or  immunocompromised  individuals  at  risk.  FeLV  can  spread  from  litter  boxes. When a host cell is infected. FeLV. the other diseases that cats  develop  because  of  feline  leukemia  could  definitely  put  young.  elderly. the amount of virus needed to infect 100 percent of a population of  kittens would infect no more than 30 percent of a similarly sized population of adult cats. H umans are not the only mammals that can develop leukemia. ♦  fel in e leuKemia by a virus.  In  fact. Unlike most forms of human leukemia. In the United States alone.  Consequently.

in the case of adult T-cell leukemia. even if apoptosis is signaled. HTLV-1 causes leukemia in a high percentage of the people it infects.externaL risk FaCtors and Causes oF Leukemia 101 The virus makes a DNA copy of its RNA genome. su mma ry There is no single cause for all types or cases of leukemia. and the Solomon Islands. Central Africa. pesticides. they can continue to divide. makes them immortal. . and. This “viral RNA” inserts itself randomly into the host cell’s DNA. The incidence of the HTLV-1 infection is not the same all over the world. Most cases of leukemia cannot. Since those cells will not die. the Caribbean Islands. benzene and certain other chemical solvents. The cells that are produced do not function normally and. Infection is usually acquired in infancy by nursing infected milk. or the sharing of contaminated hypodermic needles. South America. identifiable risk factors. as with other types of leukemia. be linked to specific. Transmission of HTLV-1 is by bodily fluids. they will crowd out healthy cells. blood transfusions. Its genetic material contains instructions that enable it to bind to T-cells and activate host genes that trigger cell division (even in the absence of growth factors) as well as block host inhibitors of cell division. however. the retrovirus HTLV-1. Known risk factors include exposure to high-energy radiation. Prevalence is highest in southwestern Japan. HTLV-1 targets T-cells. Papua New Guinea. Infection can also be spread by sexual contact. and triggers cell proliferation. Approximately 5 to 15 percent of adults are infected in these locales.

Internal responses to rIsk Factors: Genes and chromosome chanGes Key Po ints ♦ 7 Genetic disorders that affect bone marrow also increase the likelihood of developing leukemia. ♦ There are several specific oncogenes that are involved in the development of leukemia. The Philadelphia chromosome. Mistakes. If enough errors accumulate in the genes that are important for the regulation of cell 102 . Leukemia. produced by a translocation. and malfunctions occur in genes and/or chromosomes. like other cancers. is associated with the development of chronic myelogenous leukemia. is a genetic disease. defects. ♦ ♦ Dysfunctional tumor suppressor genes increase the risk of leukemia.

internaL responses to risk FaCtors 103 communication, cell division, DNA repair, apoptosis, and differentiation, a cell becomes cancerous. Scientists have accumulated a vast amount of evidence showing that gene and chromosome dysfunction can lead to leukemia. Let’s consider some of what they have learned.

other diseases that inCrease leuKemia risK
If the development of leukemia is indeed related to genetic malfunctions in blood-forming cells, one might expect that inherited genetic disorders that affect bone marrow and/or cell division might have an impact on the development of leukemia. This prediction is borne out in several diseases. Fanconi’s anemia, an inherited disease that leads to bone marrow failure, increases the likelihood of leukemia. Similarly, SchwachmanDiamond syndrome, another inherited disease, is responsible not only for an insufficiently functioning pancreas, but also for dysfunctional bone marrow and the consequent increased risk of leukemia. Bloom syndrome is another inherited disorder in which a gene mutation leads to excessive chromosome breakage. Individuals with Bloom syndrome suffer from growth deficiencies both before and after they are born, mental retardation, and extreme sensitivity to light. Also, they have an increased risk of leukemia. Li-Fraumeni syndrome is linked to the development of many types of cancer, including leukemia. In this disease, individuals inherit a mutated version of the tumor suppressor gene. Individuals with ataxia telangiectasia, an inherited immunodeficiency disease, have an increased likelihood of developing leukemia because the mutated gene interferes with the normal cellular mechanisms that prevent damaged DNA from replicating. When defective DNA replicates, errors accumulate even more rapidly. Finally, individuals with Down syndrome are also at an increased risk of leukemia. The genetic mistake

104 Leukemia in Down syndrome is the presence of an extra chromosome 21. Instead of possessing only 2 copies of chromosome 21, cells of Down syndrome patients have three; Down syndrome is also called trisomy-21. Scientists are not certain why Down syndrome increases leukemia risk but they speculate that the chromosomes might be more fragile and vulnerable to breakage. It is interesting that there is such a broad array of genetic diseases that increase the likelihood of leukemia. The only thing that all of these disorders appear to have in common is that they possess defective or malfunctioning versions of genes that are important for blood cell division, development, and differentiation. Most leukemias occur, however, in the absence of any particular inherited disease. Nevertheless, these leukemias also involve altered or dysfunctional genes. Several external factors can trigger the development of leukemia, including high-energy radiation, chemotherapy, exposure to benzene and certain other chemicals, diet, and HTLV-1. All of these causative agents also have one thing in common: They damage genes and/or chromosomes, thus increasing the leukemia risk. A person can inherit a disease that has the capacity to assault gene structure and function, and he or she can be exposed to external factors that can do the same type of genetic damage. What genes are important for regulating division in blood-forming cells?

onCoGenes and leuKemia
Peyton Rous’ discovery of a tumor-causing virus, though not fully understood or appreciated until decades later, was actually the first of many steps in the research path that led to our understanding of oncogenes and proto-oncogenes. The Rous sarcoma virus (RSV) possesses an oncogene called src, which is an altered form of a normal cellular gene,

internaL responses to risk FaCtors 105 or proto-oncogene. When cells are infected with RSV, the src oncogene produces an abnormal protein that tells the cell to undergo division. This activation of cell division cannot be turned off because the defective src protein will not respond to normal cellular signals trying to stop it. As a consequence, the infected cells become cancerous. Although oncogenes were first revealed by studying tumor-causing viruses, most oncogenes are not introduced into human cells by infection. In fact, oncogenes generally originate from a normal cellular gene that has been altered with respect to its structure and/or function. The proteins encoded by proto-oncogenes play critical roles in the elaborate, carefully orchestrated biochemical pathways that regulate cell communication, division, survival, and differentiation. When a proto-oncogene is changed to an oncogene, often due to factors that damage or alter DNA, a component of one of these pathways gets stuck “on.” If enough oncogenes are present, the cumulative errors will produce cancer. Let’s consider the general logic of those biochemical pathways and how the transformation from proto-oncogenes to oncogenes can lead to cancer. First, cells communicate whether or not to undergo division by producing chemical signals called growth factors. Normally growth factor production and release are carefully regulated. If oncogenes ensure that growth factors are continually present, cells will be signaled constantly to divide. Second, growth factors ordinarily bind to and activate receptors present in the cell membrane. When the growth factor is bound to the receptor, a signal is sent to the cell’s interior indicating that cell division should occur. An oncogene that produces an altered receptor can remain activated even in the absence of a growth factor. Uncontrolled cell division can result. Third, an activated receptor triggers the production of signaling molecules inside the cell. These molecules activate a cascade of additional signal molecules—think

the oncogene c-myc. Finally. is important in mouse leukemia. and cells remain in a perpetually dividing. tumor suPPressor Genes and leuKemia While proto-oncogenes are responsible for encoding proteins that encourage cell proliferation. undifferentiated state. trigger apoptosis. Oncogenes that produce altered gene regulatory proteins can activate and deactivate genes in a manner that keeps cells dividing. DNA errors cannot be fixed. and the human oncogenes abl. damaged cells do not undergo apoptosis. v-erb-b. which is found in chickens. PML/RAR alpha. Scientists have identified several specific oncogenes that play roles in the development of leukemia. survival. encode for receptors that continually signal bone marrow cells to divide even in the absence of an appropriate signal. Regulatory molecules control which genes are “on” and which are “off. The human oncogenes K-RAS and TEL-JAK2 each produce intracellular signal molecules that continue the pathway of communication even under inappropriate conditions. and differentiation when conditions .10 Leukemia of a “bucket brigade”—that ultimately reach gene regulatory molecules in the nucleus.” Oncogenes that perpetually produce any of these cellular-signaling molecules will activate the pathway leading to cell division. A similar oncogene that affects receptors. and PDGFR. encodes a transcription factor that regulates gene expression such that cell proliferation is activated. or promote differentiation. When these proto-oncogenes are transformed into oncogenes. For example. v-mpl. There are also proto-oncogenes that encode for normal proteins whose jobs are to repair damaged DNA. The end point of this entire communication pathway resides at the genes. found in chickens.

internaL responses to risk FaCtors 10 Figure 7. UV light. Oncogenes can activate the formation of cancer cells. the proteins produced thanks to the tumor suppressor genes halt the march toward cell proliferation. or if DNA must be repaired. If the cell needs to make additional materials so that division can proceed. tumor suppressor proteins will delay cell division. tumor suppressor genes put the brakes on these processes when necessary. If the DNA of a cell is damaged or if the cell is not prepared to divide.1  Proto-oncogenes can be transformed into oncogenes when they are exposed to  certain agents that affect their DNA. These agents might be radiation. or certain  chemicals. . are appropriate.

It is easy to see how a loss of normal p53 can lead cells to proliferate uncontrollably. cancers. For example. . p53 is lost or dysfunctional in 50 percent of all human cancers. cell division can resume. the “go” signal is delivered permanently. tumor suppressor proteins will trigger apoptosis.1. scientists have identified several specific tumor suppressor genes important in leukemia. Once the DNA has been corrected. In this way.10 Leukemia If a cell or its DNA is too damaged to repair.3 In addition to the tumor suppressor gene p53. When proto-oncogenes are transformed into oncogenes. If DNA damage is so great that it cannot be repaired. INK4 is also important in leukemia. or dysfunctional in most. p53 triggers apoptosis. However. mutated genes are not passed on to a new generation of cells. their “stop” signal can often override the information from the oncogene. encodes for a protein that together with some other molecules is able to assess DNA and chromosome damage. if tumor suppressor genes are mutated or altered. This tumor suppressor normally inhibits cell division directly and it also stabilizes p53 protein in the cell. p53 delays cell division and regulates the genes involved in repair. inactivated. a human tumor suppressor gene. In fact. Proto-oncogenes and tumor suppressor genes work together in a carefully balanced way to assure that cell proliferation is tightly regulated. if not all. If tumor suppressor genes are functional. p53. this critical stop signal disappears. The p53 protein is a transcription factor: it regulates whether specific genes are actively directing the synthesis of other proteins. Loss of INK4 function contributes to the development of leukemia and certain other cancers. As in the case for oncogenes. Scientists have observed that tumor suppressor genes are lost.2. When DNA is damaged.

 the cell is  directed to undergo apoptosis. he sPotliGht o n Ca nC e r s C ie n t is t s : s i r D a v i D l a n e . Known as the “guardian of the genome. If the DNA damage is too great. D. (1951– ) I n 1978 David Lane published a paper that changed the future of cancer  research. Mutations in the gene that encodes  p53 are present in at least 50 percent of all cancers.internaL responses to risk FaCtors 10 the PhiladelPhia Chromosome The idea that chromosomes. receiving his bachelor’s degree in 1973 and his Ph. Dr. When the DNA of a cell is  damaged  or  if  the  cell  starts  to  divide  uncontrollably. He is  presently a professor of surgery and oncology at the University of Dundee  in Scotland.  the  level  of  p53  protein  rises  in  the  cell. David Lane was knighted in 2000 for his contributions to our  understanding of cancer. he described the protein p53. The German scientist David von Hanseman examined cancer cells with a microscope and observed chromosomal abnormalities that he did not see in normal cells. He attended University College  London. In cases where the p53 gene is mutated.  As  a  consequence. P h .D. the structures in the cell’s nucleus and the physical repository of genes. in 1976. Lane was born in England in 1951. a molecule that plays a  critical role in both aging and cancer.  cell  division  is  halted  and. might be important in cancer development dates back to the nineteenth century. DNA is repaired. .  if possible.  cell division is not stopped and a tumor forms. In it.” p53 is a tumor suppressor.

of cancer was in the case of chronic myelogenous leukemia and the Philadelphia chromosome.110 Leukemia published his findings in 1890. they collected blood. Their discovery turned out to be of wide-ranging importance. or gene expression. which they named the Philadelphia chromosome after the city in which it was discovered. DNA. there are more than 200 . Interested in what was going wrong in the cells of CML patients. rather than an effect. His hypothesis was amazingly prescient. Of course. Boveri was correct.4. in the leukemic cells of other CML patients but never in normal cells. In all. In 1956 Dr. Nowell and Hungerford carefully made detailed observations of many samples. In fact. or shape of chromosomes compared to what they saw in normal cells. a German embryologist. and stained the cells with dyes in order to visualize the chromosomes. the first evidence that a chromosome abnormality could be a cause. Peter Nowell was a young assistant professor and scientist working at the University of Pennsylvania. particularly because in 1914 no one had any knowledge of the physical structure of genes. Chromosomes do play an essential role in cancer formation. In the early twentieth century Theodor Boveri. the Philadelphia chromosome is a specific example of a more general phenomenon. Boveri speculated that the “predominance” of chromosomes that promote cell division or the absence of chromosomes that inhibit proliferation was responsible for cancer. let alone tumor suppressors or oncogenes. He and his graduate student David Hungerford were studying CML. Their painstaking work paid off—in 1960 they identified an unusual small chromosome in the leukemia cells of a CML patient.5 In fact. grew the cells on microscopic slides. extended this work and in 1914 published The Origin of Malignant Tumors. size. They wanted to see whether CML cells had any changes in the number. Nowell and Hungerford found this structure.

especially leukemia. When Nowell and Hungerford were doing their experiments.2  The Philadelphia chromosome is a chromosomal abnormality caused  by the translocation of genetic material in chromosomes 9 and 22. In 1960 the  Philadelphia chromosome was linked to chronic myelogenous leukemia. chromosomal abnormalities that are associated with particular types of cancer. techniques and methods had not yet been invented to determine exactly what had changed structurally in the chromosome and how function .internaL responses to risk FaCtors 111 Figure 7.

sPot liG ht o n Ca nCer s Cie n t is t s : P e te r n ow e l l . (1928– ) Hungerford.  When he began his job at the University of Pennsylvania. He grew human leukemic cells on microscope  W hen Peter Nowell began his medical research career. several teams of scientists studying the Philadelphia chromosome and its relationship to CML learned exactly what chromosome and genes are involved and why leukemia develops. M .” meaning that they bind readily to another broken end. and when they do the broken ends are “sticky. Yet he and his colleague. After his residency training and two years  at the United States Naval Radiological Defense Laboratory. Peter Nowell was born in Philadelphia and has rarely lived away from  his hometown. Sometimes chromosomes can break. Ultimately. He earned his bachelor’s degree from Wesleyan University in  Connecticut and then returned to Philadelphia to attend medical school at  the University of Pennsylvania. over the course of decades. David  .  discovered  the  first  definite  relationship  between  a  genetic  change  and  the  development  of  cancer.  originated  the  field of cancer cytogenetics. He  has been there ever since.D.112 Leukemia was affected.  and  in  doing  so. Nowell joined  the pathology department at the University of Pennsylvania in 1956. almost nothing  was known about cancer genetics. he decided to  continue  the  studies  he  had  begun  at  the  United  States  Naval  Radiological Defense Laboratory. Nowell first developed an interest in leukemia during his residency.

 David Hungerford. a piece of chromosome 9 detaches and sticks to the broken end of chromosome 22. This translocation event occurs in bone marrow stem cells and therefore is present in all cells derived from these cells. all starting from what he calls his “stumbling”  across the Philadelphia chromosome.  that  this  chromosome  was  due  to  genetic  change  that had occurred in a single cell and that all of the offspring of this  cell also had this alteration. some of the genes on chromosomes slides and stained them with a dye so that chromosomes could be visualized and identified.  Not  self-important  in  any  way. they realized that this abnormal  chromosome. Working with a graduate student.  tiny  chromosome  not  present  in  normal  cells. When this chromosome translocation occurs.  Nowell  and  Hungerford  reasoned.  not a response to the disease. They published their findings in 1960 but  it was not until the development of molecular biological techniques in  the 1980s that scientists were able to determine exactly what happened  at the level of the DNA. Moreover.  he  seems  surprised  by  the  many  awards he has collected.  They  discovered  that  the  white  blood  cells  of  patients  with  chronic  myelogenous  leukemia  (CML)  possessed  an  odd. In the case of CML. .  Nowell examined the blood cells of individuals who suffered from acute  or  chronic  leukemias. Peter  Nowell  was  and  remains  a  cheerful  man  with  a  good  sense  of  humor.  correctly.internaL responses to risk FaCtors 113 Chromosome breakage can be caused by several external factors including exposure to high doses of radiation. was the cause of CML. called the Philadelphia chromosome.

and as a result it is transformed into an oncogene. bcr and abl. producing a 96 percent rate of remission in the early phases of CML. The presence of the Philadelphia chromosome is necessary but not sufficient for CML to progress to the more serious blast phase. One of the products of this translocation is a shortened chromosome 22 (the Philadelphia chromosome). however. are fused and produce an abnormal fusion protein. While the drug Gleevec successfully inhibits the oncogenic protein produced by the fused bcr-abl gene. the only cure is a bone marrow transplant. For this event to occur. These defects in tumor suppressor genes have not been observed in chronic phase CML or normal cells. The prognosis is poor for these patients compared to individuals who do not exhibit the Philadelphia chromosome. The two genes. the proto-oncogene abl from chromosome 9 winds up next to bcr (breakpoint cluster region) on chromosome 22. Finally. The normal abl gene encodes for a receptor that signals cell divisions if growth factor is bound to it. and in another 20 percent the tumor suppressor Rb1 is affected. and the other is a lengthened chromosome 9.114 Leukemia 9 and 22 are repositioned. It permanently signals cell proliferation even in the absence of growth factors. the Philadelphia chromosome is also seen in a subset of patients with ALL or AML. tumor suppressor gene defects have a role in the progression of CML but not in the initiation of the disease. Ninety-five percent of all CML patients exhibit the Philadelphia chromosome.6 Evidently. tumor suppressor genes must be lost or mutated. The abl proto-oncogene is not translocated in its entirety. Alterations in p53 have been observed in 30 percent of blast crisis cells. The fusion bcr-abl protein is a dysfunctional receptor. Specifically. .

Tumor suppressor genes control. oncogenes continually encourage cell division. When tumor suppressor genes are lost or damaged.internaL responses to risk FaCtors 115 su mma ry Leukemia. is a genetic disease in the sense that an accumulation of specific gene mutations is necessary for a cell to become fully malignant. stop cell proliferation. Oncogenes originate from normal cellular genes. . their ability to regulate cell division disappears. Instead of following normal growth controls. as is the case for the Philadelphia chromosome and CML. and if appropriate. like any cancer. slow. Finally. called proto-oncogenes. which were damaged or changed. Some of the types of genes that are important for the development of leukemia are oncogenes and tumor suppressors. the genetic change associated with the development of leukemia can involve the rearrangement of entire chromosomes.

Stem cell transplantation is the only method with the potential to cure leukemia. and fatigue. treatment. and preventIon oF leukemIa Key Po ints ♦ 8 Leukemia is diagnosed after a physical exam followed by blood test and a bone marrow biopsy. the most serious of which is graft-versus-host disease. The principal treatment for leukemia is chemotherapy although radiation therapy is used in some circumstances. Chemotherapy often produces side-effects including hair loss.dIaGnosIs. nausea. Stem cell transplantation sometimes produces side effects. Future treatments include the development of new chemotherapy drugs and improved stem cell transplantation therapies. 11 ♦ ♦ ♦ ♦ ♦ .

the chance of finding a suitable donor was close to zero. Cammy’s family did not give up. Her physicians indicated that Cammy’s last chance to survive was a bone marrow transplant. they saw this setback as an opportunity to help not only Cammy. She was 13 years old. the ethnicity of the donor and recipient because it increases the likelihood that the cells of both individuals have similar proteins on their surfaces. Instead. the recipient’s body can reject the transplantation. It is important to match. Next. By 1992 Cammy’s had experienced two relapses. meaning the return of her leukemia. Given the small percentage of the donor population that would be suitable for her to search. like a bolt out of the blue. treatment. In fact.2 million volunteer donors in the registry but only about 3 percent of them were Asian (like Cammy). As her physicians explained. this extra problem made Cammy’s treatment more challenging. and prevention oF Leukemia 11 Cammy Lee’s life changed completely in 1986. The odds were very much against Cammy. physicians look to biologically related family members for bone marrow donations. Unfortunately none of her siblings was a match. treatment began immediately. The prognosis was not as positive as Cammy and her family hoped because her ALL was accompanied by the presence of the Philadelphia chromosome. thereby reducing the risk of rejection.diagnosis. she had to undergo many rounds of treatment because her leukemia would not remain in remission. There is generally a 20 percent chance of a good bone marrow match between siblings. but others in her situation as well. as much as possible. Cammy’s family and physicians turned to the National Marrow Donor Program. Cammy underwent radiation therapy and extensive chemotherapy. Cammy had five siblings so everyone assumed that at least one would be a suitable donor. Since her leukemia was an acute rather than a chronic form. . enjoying the start of her teen years. There are more than 1. she was diagnosed with ALL. If the match is not a good one. when. Ordinarily.

have been amazingly successful. they actually began to recruit donors for an organization they created called the Cammy Lee Leukemia Foundation (CLLF). She graduated from Rutgers University in 1999. The first clues that something is wrong include fatigue that will not go away.000 minority donors have been registered in the National Marrow Donor Program. Their work and determination paid off. The physician or nurse collects a blood sample. a greater than ordinary frequency of colds and other infections. most of them not serious. and if so. what type of leukemia and what treatments to begin. thus giving hope and a chance to a wider array of people than ever before. but a physician would probably order tests to see if leukemia is the problem. more than 100. or in lymph nodes. Cammy resolved to live her life fully and meaningfully. There are many possible causes for this array of symptoms.11 Leukemia They searched for donors beyond the National Marrow Donor Program. Since the start of the foundation. and those of her colleagues. a Chinese-Canadian mother of three. In fact. in 1992 Cammy found a match. and swelling in the left side of the abdomen where the spleen is located. Cammy and Virginia met in 1994. further tests and other diagnostic methods are undertaken to determine whether that person has leukemia. which is examined by medical technologists. The first tests would examine the blood cell population in the patient’s body. Her efforts. She works full time as the recruitment manager for the CLLF. Virginia Lau. The blood will be examined .1 how is leuKemia diaGnosed? Once a patient is suspected of having leukemia. saved Cammy’s life by donating bone marrow.

stain them with dyes. shapes. Technologists compare the color pattern in leukemic cell chromosomes with that of normal cell chromosomes to see whether any genes have changed position. Lots of chromosome damage or gene rearrangement indicates a more troubling prognosis. The prognosis and treatment plan for an individual depends on the degree of genetic change that is present.diagnosis. treatment. In this way. taking . Although physicians can learn a great deal from these blood tests. Medical technologists use cytogenetics and a method called fluorescence in situ hybridization (fiSH) to examine the cells. and prevention oF Leukemia 11 microscopically as well as through the process of flow cytometry. the number of red blood cells and each of the types of leukocytes can be determined. or sizes are different from what they observe in normal cells. Flow cytometry enables the technologist to determine whether the number of each type of blood cell is in the healthy range or if there is a deficit or overabundance of a particular cell type. Unlike blood collection. With cytogenetics. This test takes advantage of the fact that different types of leukocytes vary with respect to the specific proteins present in their cell membranes. as one would see in leukemia. and examine the chromosomes to see if the number. technologists attach leukemic cells to slides. thus producing a striped pattern. physicians also need information about the genes and chromosomes in the leukemic cells. If there is an excess of leukocytes. the final piece of information they need to confirm a diagnosis of leukemia is found in the bone marrow. In addition to determining blood cell counts and identifying the affected cells. Identifying exactly which kind of leukocyte is producing leukemic cells is essential for accurate diagnosis as well as for planning treatment. which separates the cells into different groups. FISH is a technique in which chromosomes are stained with a series of differently colored dyes. immunophenotyping is done.

and treatment plan. or chemotherapy. prognosis. physicians need to know what cells are affected in the bone marrow so they can establish an accurate diagnosis. Fortunately. the cells are examined with the same methods used to evaluate blood samples. A method similar to aspiration is used to collect large amounts of marrow. Once the marrow is collected. the physician uses an anesthetic to numb the location from which bone marrow will be collected. The goal of treatment is to remove cancer cells and to kill any cancer cells that might remain.120 Leukemia a bone marrow sample is a somewhat complicated and uncomfortable process. As is the case for the blood tests. how is leuKemia treated? Physicians attack most cancers with one or a combination of the following: surgery. surgery is generally not an option because blood cancers are more diffuse throughout the entire body than solid tumors. In the case of leukemia. The physician inserts a very thick needle into a large bone and removes both marrow and some bone. as well as their possible side effects and some new avenues for therapy that are being developed. chemotherapy is by far the primary tool used to fight leukemia. a relatively fine needle is inserted into a large bone in order to remove some marrow. radiation therapy. Blood cancers cannot easily be “removed. There are two methods available for collecting bone marrow. we will consider these treatments in more detail. For some cases. many leukemia patients have one more option that offers the potential for a cure—stem cell transplantation. With aspiration.” Although radiation therapy is often used with other treatments. chemotherapy provides only temporary remission. . In the sections that follow. Because it is a painful procedure.

A case from 1930 describes a 60-year-old man with CML who was given 10 series of radiation treatments over a period of twoand-a-half years.diagnosis. spleen. They defined the erythema dose. The strategy of this therapy is similar to that of radiation therapy—kill the abnormal cells. dry. radiation therapy is done daily. due to their repeated unprotected exposure to radiation. tender skin at the sites of exposure. The observation that arsenic could eliminate skin cancers led scientists to ask whether other cancers might be treated with similar success. including cancers. aims a high-energy X-ray to the site of a tumor. the radiation exposure required to produce pink skin that resembles but is slightly less than a sunburn. Unfortunately. radiation was the treatment of choice for leukemia. A patient may receive radiation on the whole body or directed at the brain. In the early twentieth century. for six to eight weeks. thus killing the cancer cells. or other area of the body where leukemia cells have collected and formed a tumor. and prevention oF Leukemia 121 radiation The first clinical radiologists used their arms to determine the appropriate dose for patient therapy. potential side effects include fatigue and red. five days a week. a commonly used form of radiation therapy to treat leukemia. with caustic arsenic pastes. . Generally. Although the treatment itself is painless. External beam radiation. He received two-thirds of an erythema dose delivered over his spleen every three months. This method of treating skin cancers persisted into the twentieth century. Chemotherapy The ancient Egyptians treated superficial skin lesions. treatment. these radiologists developed leukemia at a frequency much higher than the general population.2 Radiation therapy now used to treat leukemia is more refined.

In one case. the leukocyte count rose to abnormal levels. Fowler’s solution became the primary therapy for CML until it was replaced by radiation and other chemotherapy drugs. A larger study of 10 patients suffering from CML was done at the Boston City Hospital in 1931. they all relapsed within weeks. the type of medication used depends on the specific . Scientists studying the mechanism of arsenic action have demonstrated that this therapy inhibits cell proliferation and encourages apoptosis in leukemic cells. this treatment of leukemia experienced a rebirth in China in the 1970s. When administration of Fowler’s solution was stopped. Unfortunately. When the arsenic trioxide therapy was discontinued. In fact. enlarged spleens shrunk to normal size. This new. demonstrated that administering arsenous tri-oxide in the form of a topical medication called Fowler’s solution eliminated leukemia in his patients. normal blood cell development resumed in the bone marrow. the leukocyte number went down. Amazingly. Arsenic therapy declined dramatically in the early twentieth century. whereas other types of chemotherapy drugs are used for different leukemias. the leukocyte counts approached normal levels in a patient treated for 10 weeks. lower-dose version of arsenic therapy is safe and very effective for all stages of APL. Physicians have been using arsenic trioxide as one aspect of treatment for APL. the majority of the patients ultimately experienced chronic arsenic poisoning. Of the 10. Arsenic trioxide is certainly an effective component for treating APL. In 1878 scientists described the response of patients’ leukocytes to Fowler’s solution. and the patients experienced a sense of well-being.3 Nevertheless.122 Leukemia In 1865 Heinrich Lissauer. a German physician. When Fowler’s solution was once again given to the patient. nine responded to arsenic trioxide treatment. a subtype of AML. Their leukocyte counts became normal.

 an arsenic  compound. In 2000 the FDA approved Trisenox. L ong associated with poisoning. Generally. a skin inflammation condition. arsenic has returned  to the modern pharmacy. People claimed that Fowler’s solution could  treat various diseases including epilepsy and headaches. It  is important to realize that long-term exposure to even small quantities of  arsenic can result in serious side effects such as hair loss.  and  problems  with the heart and circulatory system. although other dividing cell populations in the body are also affected. and prevention oF Leukemia 123 ♦  ar seniC: Po iso n o r C ure ? though a large dose is inevitably fatal. arsenic  has been used to treat skin ailments. smaller amounts of arsenic produce  tissue  inflammation  but  not  serious  illness. digestive system  distress. and. A sore forms. chemotherapy interferes with some aspect of cell division or survival. some forms of . the cellular lining of the digestive system. in males. developing sperm. Al- leukemia. including cancers. and when it sloughs off  presumably healthy cells underneath become visible. arsenic kills surface cells.  When  applied  externally  to  the skin. These populations include hair follicles. Interestingly. Dermatologists  through the 1960s continued to recommend the external use of Fowler’s  solution for the treatment of psoriasis. As a consequence. arsenic was also commonly used in a tonic  form called Fowler’s solution.diagnosis. In addition to external use.  inflammation  of  the  body’s  mucous  membranes. The idea is to target leukemic cells. treatment. both accidental and deliberate. In this way. arsenic    has also been used throughout history to treat various ailments. to treat individuals with acute promyelocytic leukemia (APL).

This device is a special type of catheter that can be placed under the scalp so drugs can be delivered directly to the brain. This research strategy was very successful. or to divide. and gemtuzumab ozogamicin (Mylotarg). Many of these drugs stop leukemic cells from dividing by interfering with their DNA. scientists reasoned that drugs that disable this protein might be able to halt CML. and loss of fertility. The loss of fertility may or may not be permanent. Some medicines can be swallowed but others need to be delivered intravenously directly into a blood vessel. and the nausea can be treated. Some patients receive their drugs through a catheter. children and even adults sometimes use an ommaya reservoir. . Gleevec was designed to target the abnormal tyrosine kinase and halt its activity. and other have drugs injected directly into the spinal fluid. Because CML cells produce an abnormal receptor molecule called tyrosine kinase that permanently activates cell division. Others attack specific proteins that the leukemic cells need to live. Chemotherapy drugs need to reach the brain and spinal cord if leukemic cells are present there. nausea.124 Leukemia chemotherapy produce side effects such as hair loss. Chemotherapy is administered to the patient in various ways. although spinal injection works in many cases. The hair loss and nausea are temporary. That is exactly what Gleevec does. There are more than 50 different types of chemotherapeutic agents that are used alone and in various combinations to treat leukemia. is very effective at producing remission in early-stage CML. Imatinib mesylate. depending on the drugs being used. placed in a large vein. also called Gleevec. or tube. Examples of three newer treatments that are more specialized for particular leukemias are imatinib mesylate (Gleevec). These medicines are probably in the first generation of treatments that target leukemic cells rather than all dividing cells. tretinoin (Vesanoid).

Mylotarg is a specific antibody molecule that recognizes and binds to a particular membrane protein found on AML cells. ATRA is an important signal molecule used in cell differentiation during normal development. other cells are generally not affected. is yet another focused strategy. Because the treatment is so focused. stem Cell transplantation In some cases. As a consequence. leukemic cells sometimes develop resistance to chemotherapy drugs and the cells begin to proliferate once more. This drug is a type of molecule called all-trans retinoic acid (ATRA). would promote the differentiation of immature leukemic cells into more mature functioning ones. Interestingly.diagnosis. it may be necessary to do a stem cell transplant. the leukemic bone marrow of the patient is destroyed and healthy bone marrow. . Unfortunately. Gemtuzumab ozogamicin. In this case.” meaning that attached to it is a deadly toxin. containing stem cells. often sold as Mylotarg. like Vesanoid. Other chemotherapeutic agents will be tried but ultimately. chemotherapy produces permanent remission. The hypothesis was correct: Vesanoid does indeed trigger differentiation of the leukemic cells. undifferentiated state. When Mylotarg binds to the leukemia cells. drugs administered at regular intervals for the rest of the patient’s life. if the Vesanoid treatment ceases to be effective. they are in for a big surprise. In this procedure. the second line of treatment for APL is arsenic trioxide (Trisenox). is first-line treatment for APL. Mylotarg can bind specifically to leukemic cells and kill them with its deadly cargo. Scientists speculated that leukemic cells are generally “stuck” in an immature. also sold as Vesanoid. For other patients. treatment. is a drug used to treat AML. Mylotarg is “weaponized. and prevention oF Leukemia 125 Tretinoin. remission is stabilized by maintenance chemotherapy. They hypothesized that treating APL with differentiating agents.

1a  If chemotherapy has not worked.12 Leukemia Figure 8. an autologous stem cell transplantation is  the preferred method of destroying leukemic cells and replacing them with healthy cells. which means that the body will not reject the transplanted cells. The  patient is the donor. .

Physicians collect stem cells from a leukemia patient who is in complete remission. . These cells are frozen until they are needed. the patient remains vulnerable to infections and bleeding during that time. however. Successful stem cell transplantations actually cure leukemia. and prevention oF Leukemia 12 is collected from a donor and transplanted into the patient. Cells use these proteins for many different functions including cell recognition and communication. healthy leukocytes to occur. There are several strategies for getting a good stem cell donor match. Because it can take up to two weeks for the first new.” All of the cells in a given person have the same types of proteins indicating “self. treatment. because the procedure entails some risks and side effects can be difficult. The most desired approach is to do an autologous transplantation. which identify themselves as “nonself. After completion of this step. In fact. tissues or cells transplanted from another body will possess a different set of proteins. In contrast. the recipient’s immune system will kill the transplanted cells. some of these cell membrane proteins allow the body to recognize “self” versus “nonself. These transplantations are not the first choice for treatment. the physician administers total body irradiation and chemotherapy to kill all cancer cells. All cell membranes contain a wide variety of embedded proteins. the body’s immune system does not attack its own cells. This behavior occurs when the body rejects a transplanted organ. in which the recipient is also the donor.” As a consequence.diagnosis. and transplantation is the next appropriate treatment.” For this reason. If the patient relapses. Successful transplantations require a good “match” between the donor tissue and recipient tissue. the physician reinfuses the previously frozen stem cells.

1b  In an allogenic stem cell transplantation.  there is a chance that the patient’s body will reject the transplanted cells.12 Leukemia Figure 8. a donor who is not the patient  provides healthy stem cells. Although donors are carefully screened to match the recipient. .

As a consequence. Next. an individual receiving an allogeneic transplantation needs to take additional medicines to suppress his or her immune system’s response to “foreign” cells. physicians would next check the National Marrow Donor Program. The stem cells are frozen for later use. other blood relatives would be tested. The best allogeneic match is one between identical twins. treatment. blood collected from the umbilical cord and . Finally. the patient is at risk for infections and bleeding during this time period. Stem cells are also harvested directly from the blood. Also. it takes a while for normal leukocytes to appear—two to three weeks for an allogeneic transplantation. The physician injects the donor with a growth factor for four days. and prevention oF Leukemia 12 Often. the greater the chances for success and the fewer side effects. Instead. allogeneic transplantations are performed. In the absence of a good donor in the patient’s family. To use this method. stem cells need to be “mobilized. As is the case with autologous transplantations. Stem cells are collected daily during this mobilization treatment. The donor is someone other than the recipient.diagnosis. This organization maintains a searchable record of tissue-typed volunteers so that matches can be found for unrelated donors. the physician treats the patient with whole-body radiation and chemotherapy to kill all cancer cells. autologous stem cell transplantation is not possible. the stems cells collected from the donor can be transfused into the patient.” or moved from the bone marrow into the blood. The most usual location for collection is the bone marrow. Next. Once a donor is located. The closer the tissue match between donor and recipient. There are several sources for stem cells to be used in transplantations. the tissue where blood-forming cells are found.

 Dr. (1940– ) Uniformed Services University of Health Sciences and at the University of  Washington School of Medicine and Health Sciences. as well as a Professor of Surgery at the  . Rosenberg is the Chief of Surgery at the National Cancer Institute   (NCI) in Bethesda.  Rosenberg developed interleukin-2. He has had some amazing achievements in this area. He also received a Ph. Research is under  way to see whether it is possible to develop antibodies that will specifically  recognize  cancer  cells  and  mark  them  for  destruction. Occurring in recipients of allogeneic transplantations.D. For example. P h . in biophysics from Harvard University.  Finally. The principal long-term side effect of stem cell transplantation is graftversus-host disease (gVHD). D. in which the body’s immune system is helped in its fight against  cancer cells. Rosenberg and his team have identified more than two dozen  types of molecules associated uniquely with cancer cells. He also identified a type of  white blood cell that invades tumors and figured out how to use these cells  against cancer. as  the first immunotherapy treatment for cancer. Steven Rosenberg  has devoted his life to the understanding and treatment of cancer. D.  He became Chief of Surgery at NCI in 1974 and has been there ever since. GVHD is a consequence of the immune system’s response to sPot liG ht o n CanCer sCie n t is t s : s teve n a. Rosenberg earned his bachelor’s and medical degrees at Johns Hopkins  University.130 Leukemia placenta contains fetal stem cells. Rosenberg has been a pioneer in developing immunotherapy for cancer  treatment. Blood can be recovered from these tissues and frozen for later use. M . a natural molecule made by the body.  Rosenberg  S teven A. Maryland. r o s e n B e rg .

 the results  were spectacular. For  two of the patients.2  Dr. .    (National Cancer Institute/U. National Institutes of Health) .  these  individuals had been told that  they  would  live  for  no  more  than  another  3  to  6  months.diagnosis. their cancers  were  completely  eliminated. hardening skin. joint stiffness.S.  As  Dr. As one leukemia patient characterized—it is like trading one disease for another.  Before  the  experiment.”4 Figure 8. nausea.  He  took  normal  white  blood  cells  from  17  patients  with  malignant  melanoma. “This is just a start . difficulty swallowing. treatment.  Rosenberg says. As the body attacks the offspring of the transplanted cells. . GVHD can range from mild to life threatening. symptoms can include skin rashes. dry or irritated eyes. diarrhea. did the first clinical studies of  gene  therapy  to  fight  cancer. Steven Rosenberg. vomiting.  The  white blood cells were modified  so  that  they  would  recognize  the deadly melanoma cells. and liver damage. . and prevention oF Leukemia 131 foreign cells. [W]e’re working around the clock  to try to improve this.  Since  the  treatment  these  subjects  have  been  cancer  free for years and continue to  be  checked  regularly.

the patient’s own stem cells are diminished but not completely knocked out by radiation and chemotherapy. a type of blood cell disease. With this method. As already discussed. Instead of a graft-versus-host attack. In addition. It is effective in the subtypes of leukemia that exhibit an abnormal change in chromosome 5. a type of CLL. For example. There are also newer drugs that are either available or in development. Also. The standard method. a physical event that is very difficult to tolerate. destroys the patient’s immune system and blood cells. The advantage of this new type of transplantation compared to the methods presently used is that the patient can handle it more easily. this drug inhibits the abnormal oncogenic protein produced by bcr/abl. The donor cells are transplanted into the patient and immunosuppressive drugs are used to prevent rejection. research is under way to develop a vaccine against cancer cells. Others are still in the research and development phase. unlike this new one. is responsive to the drugs cladribine and pentostatin.132 Leukemia future treatments Scientists and physicians continue to engage actively in research aimed at improving therapies for leukemia. The idea is for the donor’s cells to establish themselves and produce normal leukocytes that will attack the leukemic cells. A new type of stem transplantation that is still in the experimental phase is called non-ablative allogeneic stem cell transplantation. Some of the newer treatments that have been developed are already being used for patients. hairy cell leukemia. Revlimid is used to treat myelodysplastic syndrome. One of the most successful drug development efforts in recent years produced Gleevec. The strategy of targeting the products of oncogenes is a powerful one and has also worked for other . scientists predict a “graft-versus-leukemia” effect.

benzene and certain other chemicals. which is encoded by an oncogene. an analysis of blood. interferons. however. and prevention oF Leukemia 133 cancers. can be administered to patients to help them regenerate bone marrow after a bone marrow transplant. Because cancer is the result of accumulated genetic errors. If this event occurs. Although techniques for early and accurate diagnosis as well as for effective treatments continue to improve.diagnosis. This drug targets a faulty receptor protein. For leukemia. the best action is early detection followed by sensible. The interferons fight the cancer cells and stimulate the body to produce more of its own interferon. molecules normally made by the immune system to fight disease. In most cases. treatment. aggressive treatment and care. everyone bears some chance of developing this disease. leukemia develops with no clear indication of any specific trigger. molecules that normally function as signals to direct blood cell production and development. smoking. can be given in higher doses to leukemia patients. Physicians examine the blood and bone marrow to see if abnormal leukocytes are . hematopoietic growth factors. the best approach for leukemia or any other cancer is to take steps to prevent its occurrence. For example. su mma ry A diagnosis of leukemia is based on a physical examination of the patient. For example. scientists and physicians are also developing treatments that take advantage of some of the self-protective features of the body itself. and a bone marrow biopsy. and infection with HTLV-1. Finally. Also. the drug trastuzumab (Herceptin) is effective for treating certain types of breast cancers. the known principle risk factors include exposure to high doses of radiation. These factors can generally be avoided quite easily.

134 Leukemia present. The only certain cure for leukemia is a successful stem cell transplant. most cases of the disease cannot be attributed to a particular cause or event. The results of these tests are essential for physicians to identify exactly what type of leukemia has occurred and to plan appropriate treatment. patients achieve long-term remission. Scientists are hard at work developing new. . In some cases. Although some risk factors for leukemia have been identified and should be avoided when possible. If such cells are observed. the specific type of leukemia cell is identified and the medical technologist can analyze chromosomes to see if they are normal. Chemotherapy is the main option for all forms of leukemia. but this procedure has its own risks. more targeted drugs for leukemia as well as improved methods for stem cell transplantation.

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gLoSSary ♦ abscess A localized collection of pus in the body. an interval following the chronic phase in which cells accumulate genetic errors and produce more abnormal affecting cells of the lymphoid lineage. generally surrounded by inflamed tissue. autologous Transplantation of stored stem cells from a person back into his or her own body. A protein molecule made by the immune system that can bind to invading. accelerated phase cells. or other foreign material. acute lymphocytic leukemia (all) A fast-growing type of leukemia In CML. microorganisms. Condition in which there is an inadequate amount anemia. apoptosis aspiration Programmed cell death. A genetic disorder associated with immune ataxia telangiectasia system problems and loss of muscle coordination. acute myelogenous leukemia (aml) A fast-growing type of leukemia affecting cells of the myeloid lineage. angiogenesis antibody The growth of new blood vessels. 140 . acute promyelocytic leukemia (aPl) A subtype of AML. anemic of hemoglobin and erythrocytes in the blood. Removal of bone marrow with a fine needle. and disable them. allogeneic Transplantation of stem cells from a donor into a host.

for example. cervix The neck of the uterus. Examining a cell or tissue sample to determine if cancer is present. bone marrow The spongy material inside bones where blood cells are formed.gLossary 141 autopsy Dissection of a cadaver to determine the cause of death and the effects of disease on the body. which connects the uterus to the vagina. carcinogen carcinoma catheter A tube inserted into a blood vessel or body cavity. capillary The smallest type of blood vessel in the body. Bloom syndrome An inherited disorder in which chromosomes exhibit a high frequency of breakage. B-lymphocytes produce antibodies. like a wart. basophil benign biopsy A type of leukocyte derived from the myeloid lineage. A noncancerous tumor. bloodletting Discredited practice of removing blood to “balance” fluids of the body and to remove “bad” materials. . B lymphocyte A type of leukocyte derived from the lymphoid cell lineage. basal cell carcinoma A type of skin cancer that is usually not serious and rarely metastasizes. blast crisis In CML. Cancer of epithelial cells. the most serious stage of the disease. A substance that causes cancer. which if untreated will be fatal. cancer The uncontrolled cell proliferation and breakdown of proper cell behavior that results in the development of tumors that can spread throughout the body.

Eosinophils release chemicals to destroy parasites such as worms. leukemia affecting cells of the myeloid lineage. The structures in cells that carry the genes. differentiation Dna information. clonal vidual cell. dermatologist structures. cytogenetics leukemia affecting cells of the lymphoid lineage. A slowly progressing type of A slowly progressing type of chronic lymphocytic leukemia (Cll) chronic myelogenous leukemia (Cml) chronic phase disease. Down syndrome A developmental and physical disorder in which an individual inherits three copies of chromosome number 21 rather than two. clone. In CML. The specialization of cells into specific types of cells.142 gLossary chemotherapy chromosomes The treatment of cancer with drugs. Dendritic cells activate lymphocytes. eosinophils A type of leukocyte derived from the myeloid cell lineage. A physician who specializes in skin and related Deoxyribonucleic acid. the molecule that carries genetic . electron microscope A device that focuses an electron beam and magnifies so we can see structures as small as the parts of cells and large molecules. dendritic cell A type of leukocyte derived from the myeloid lineage. the initial slowly progressing stage of the Genetically identical cells all originating from one indiThe examination and analysis of the structure of chro- mosomes in cells.

erythrocyte Red blood cells. hemoglobin hirudin Protein in red blood cells that carries oxygen. hematopoesis. erythema dose Refers to the amount of radiation required to produce redness of the skin. histology The study of cells and tissues. often by the injection of a vaccine. graft-versus-host disease (gVHD) A potential side effect of allogeneic cell transplantation in which the transplanted cells attack the host cells.gLossary 143 epithelium. immunophenotype A technique to determine what type of lymphocyte is abnormal in ALL or CLL. immunization The process of inducing immunity. . epithelial Refers to cells organized into a sheet of tissue. fanconi’s anemia A type of congenital anemia characterized by a A type of staining deficiency in all types of blood cells. The development and differentiation Protein in leech saliva that prevents blood clotting. genome All of the genes in a cell nucleus. granulocyte Any type of leukocyte-containing granules. fluorescence in situ hybridization (fiSH) method used to analyze chromosome structure. flow cytometry A technique that separates a mixed population of cells into its constituent types. histamine Chemicals released by basophils that trigger inflammation. gene Inherited instructions composed of DNA. hematopoetic of blood cells.

leukocyte White blood cell. A genetic disorder that increases the risk of li-fraumeni syndrome lumbar puncture lymphoid developing several types of cancer. leukapheresis leukemia of abnormal leukocytes. A type of cancer or malignancy that involves the white Self-renewing cells that give rise to leukeblood cells.144 gLossary immunotherapy Using the body’s own immune system as a tool to fight cancer cells. spleen. and liver. and T lymphocytes. warm. leukemic stem cells (lSC) mia cells. One of the lineages of the pluripotent stem cells found in the bone marrow. interferon Molecules produced by the immune system to fight disease. incidence The frequency with which an event occurs. A procedure in which a needle is inserted into the spinal column and spinal fluid is removed. inflammation A local response to tissue or cellular injury wherein tissues become red. it produces natural killer cells. B lymphocytes. and swollen. of the lymph nodes. lymphoma macrophage malignant A type of cancer or malignancy involving the enlargement A type of leukocyte that eats bacteria and dirt. invasive Refers to the spread of cancer cells from one part of the body A technique used to filter blood to reduce the number to another. . Cancers that grow uncontrollably and spread to other tis- sues in the body.

the covering of the brain and spinal cord. meningioma A tumor of the meninges. A health care professional who performs lab medical technologist tests and analyses of cells and tissues. mutation A change or error in DNA. . myeloid One of the lineages of pluripotent stem cells found in the bone marrow. basophils. monocytes A type of leukocyte produced by the myeloid cell lineage. the nasopharynx. Monocytes produce macrophages. megakaryocyte Blood cells derived from the myeloid lineage that gives rise to platelets. monocytes. invasive skin cancer. A disease characterized by the inad- myelodysplastic syndrome equate production of blood cells. melanoma A highly aggressive. neutrophils. neutrophils A type of leukocyte derived from the myeloid cell lin- eage. and dendritic leukocytes. metastasis The spread of a cancer from a primary tumor to other places in the body. which produces erythrocytes. Neutrophils eat invading bacteria. eosinophils. megakaryocytes.gLossary 145 median The middle of a range of numbers. natural killer (nk) cells A type of leukocyte produced by the lymphoid cell lineage. myeloma A type of bone marrow cancer. Refers to the nose and pharynx. nasopharyngeal cavity behind the mouth and nose.

oncogene Cancer-causing gene. proliferation . pluripotent prognosis duce various cell types. nucleus Cell organelle in which chromosomes are located. A physician who specializes in cancer. The study of disease. A technique in which the patient’s own stem cells are diminished but not eliminated ommaya reservoir A type of catheter inserted under the scalp that can deliver drugs to the brain. Cell fragments that play an important role in blood clotting. phagocytic. plasma platelets The liquid portion of blood. pernicious anemia vitamin B12.14 gLossary non-ablative allogeneic stem cell transplantation completely before receiving stem cells from a donor. Cells that are not fully differentiated and which can proA prediction about the course of a disease. and that delivers oxygen and nutrients to the embryo or fetus. Cell division to produce new cells. phagocytosis microorganisms or debris. A severe anemia caused by the inability to absorb A behavior in which cell cells eat other intestine and the hormone insulin into the blood. An organ that secretes digestive enzymes into the small A physician who specializes in the study of disease. placenta The organ found in mammals that attaches the embryo or fetus to the uterus. oncogenic oncologist pancreas pathologist pathology Cancer causing.

or particles. A protein that binds to another molecule to initiate some sort of cellular response. muscle. retrovirus A type of virus that has an RNA rather than a DNA genome. signal molecule A molecule that operates either inside or outside cells to mediate cell communication. psoriasis A skin inflammation condition. or differentiation. A type of cancer from bone. radiation therapy radioactive receptor The emission of radiation from atoms. spleen Organ in which lymphocytes form. The treatment of cancer with radiation. proto-oncogenes Normal cellular genes that encode molecules regulating cell division. Cancer that forms at a site other than secondary cancers or tumors the original location of a tumor. A genetic condition character- Schwachman-Diamond syndrome scrotum. scrotal ized by an improperly functioning pancreas and bone marrow.gLossary 14 proteins Molecules in cells that are essential for cell structure and function. survival. or connective tissue. remission A decrease or cessation of a disease. rous sarcoma virus (rSV) sarcoma An example of a tumorigenic virus. Refers to the skin that encloses the testes. rays. These can be altered to become oncogenes. because of metastasis. . radiation Energy transmitted as waves. rectum The last section of the large intestine extending from the colon to the anus. relapse The return of a disease thought to be absent.

tumor suppressor ment of a tumor. virus A parasite much smaller than a cell. An enzyme essential for DNA repair. T lymphocyte A type of leukocyte derived from the lymphoid lineage. A type of kidney cancer that occurs in children. Wilms’ tumor X-rays A relatively high-energy form of radiation. A substance that stops the growth and developProteins that regulate gene activity. The windpipe. T-lymphocytes make antibodies. . and that have the ability to make various cell types. tropical anemia A type of anemia due to nutritional deficiencies and/or hookworm infestation. vaccination Treatment in which weakened or dead diseasecausing microorganisms are administered to prevent infection with a specific organism. tyrosine kinase A type of protein involved in cell communication.14 gLossary stem cells Self-renewing cells that are not differentiated. tissue A group of functionally and structurally similar cells. tumor An abnormal mass of cells. topoisomerese ii trachea chi of the lungs. vaccine. the tube that connects the larynx to the bron- The movement of a piece of chromosome to another The changing of a cell from a healthy to a cancerous chromosomal position. transcription factors translocation transformation one.

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64 common in children. 54. 58. 55 accelerated phase. 70 acute promyelocytic leukemia (APL). 52. 125 adult T-cell leukemia.” 21 bloodletting. 128. 12–13 sample. 77. 65 appendicitis. 122 Boveri. 86 basophil. 98 blast crisis. 103 ATRA. leukemia causes of. 43 bone marrow biopsy. 99 Bang. 18–19. John. abl gene abscess. 38–53 described. 64 subtypes. See also childhood leukemia. 78–79. 62–64 diagnosis. 28 Bloom syndrome. See leukemia cell counts. 27. 43. 48 bcr/abl gene. 59 treatment. See also leukemia age of onset. Oluf. John Hughes. 70 acute myelogenous leukemia (AML).. 65 actinomycin D. 103 B lymphocytes. 62. 41. 127 autopsy. 110 12 . 64. 88. 129 all-trans retinoic acid (ATRA). 12. 133 biopsy. 30–31. 65–66 blood cancer of. 122 treatment. 126. 97 basal cell carcinoma. age and. age of onset ALL. C. See acute myelogenous leukemia anemic condition. 72. 116. 80 B Baltimore. 31 Ayurvedic medicine. 133 blood cell formation/development. 37 benzene. 83 AML. 123. 41. 101. 34 aspiration. 61. 81 described. 98 Bittner virus. Theodor. 125 aminopterin. 63. See all-trans retinoic acid Australopithecus. See genes. 94–95. 118–119 cell development and function. 75. 62 causes of. 117 type of leukemia. See genes. 62. 57. 74. 20–21 proliferation of — cells. 54. See cancer. 83 described. 50 arsenic. biopsy Bittner. 6 autologous stem cell transportation. leukemia. 96. 122. 62 risk factors. 19. 123 arsenic trioxide therapy. 63. 83 acute lymphocytic leukemia (ALL). 72–73 Borgomano. 64 common in children. 56. bcr gene benign tumor. 74. bcr/abl gene bcr gene. 18. 104. 88. 119–120 stem cell source. 94 Boston City Hospital. 14 Bennett. 47 APL. 58. 62. 120 ataxia telangiectasia. David. 129 transplant. 122–123 asbestos fibers. 80 antibodies. 17 angiogenesis. 58. See acute lymphocytic leukemia allogenic stem cell transportation. 99–100. See acute promyelocytic leukemia apoptosis. 63. 56–57 defined. 22 “blood drives. 125 type of leukemia. 101 age and cancer. See also bone marrow. See genes.index ♦ a abl gene. 85–87.

124 type of leukemia. 115 in children.” 79 capillaries. See Cammy Lee Leukemia Foundation clone. 67–68. 100 cells theory.index 13 brain tumor. 64. 32–33 types of. 48. 58–59 blood sample from. 24–33 life expectancy. 64–70 phases of. 117 chronic lymphocytic leukemia (CLL). 64. 34–35 cytogenetics. 34 C Cammy Lee Leukemia Foundation (CLLF). 74. 101. 114 described. 54–55 cancer age and. 132 Children’s Hospital (Boston. 74 common in atomic bomb survivors. 67–68 chromosome 22. 61 treatment. 124 as treatment. 109–114. exposure to. 69. 13 Cellular Pathology as Based Upon Physiological and Pathological Histology (Virchow). 34. 7. 116. 12 history of. 87 treatment. 25. 104 defined. 86 breakpoint cluster region. 54 causes of. 72. 81. 113. 61. 25 Burkitt’s lymphoma. 61 race and —. 110–113. 81. 64–66 risk factors. 132. 33 carcinogen. 94–97. 61 survival rates. 84–87 in twins. 72–73 . 70 chronic phase. 120. 45 side effects. 84 chicken leukemia. 76. 88. 9 childhood leukemia. 64 described. 87 treatment. 56. See treatment “cancer cluster. 132 clinical trials. 74–76. 122. acute myelogenous leukemia causes of. 60. 6. 6–7. cancer of. 59 family patterns. 123 cladribine. 58–61 diagnosis. MA). 84 described. 54. 52 Cohnheim. 64 circulatory system problems. 34–35 secondary cancer. See also leukemia age of onset. 67. 71. 18 catheter. 116. 134 Chernobyl nuclear accident. 86. Peter. 54. 90 A Counterblaste to Tobacco (James I). 27 consolidation therapy. 61. 54. radiation. 13–15 patterns of. 64 cell damage in. 76 types of. 71. 85 contamination. 24 diagnosis. 76–77 gender incidences. Julius. 97. 12 field of. 121–125. See also acute lymphocytic leukemia. 85. 34 carcinoma. 115. 69 treatment. 36 causes of. 27. 82 chromosomes changes in. 25 chemicals. 71. 81. 70 chronic myelogenous leukemia (CML). 74 risk factor. 118 Campbell. 61 type of leukemia. 84 symptoms of. 33 cervix. 77–78. 16 Philadelphia chromosome. See bcr gene breast cancer. 112 defined. 72. 124 cats and leukemia. 84. 77–81. 102–115 chromosome 9. 60–61 risk factors. 102. 52 connective tissues. 66 CLLF. 91 described. 57. 104. 60. See also leukemia age of onset. 71. 23. 86 “Case of Hypertrophy of the Spleen and Liver” (Bennett). 133 chemotherapy “collateral damage” from. 7 overview of.

27. 43 deoxyribonucleic acid. 18 FeLV. Paul. 84 G Galen. 69 “fire drill. 109 Hart. 28. 82 Harvard University. 37 curcumin. David. 110 flow of genetic information. 122. P. 98 growth hormone production. 44–45 electrical power plants. 17–19. Philip. See Food and Drug Administration feline leukemia. side effect of treatment.. 46. 13. 103–108. 90 Fanconi’s anemia. 132 graft-versus-leukemia effect. 41. See DNA dermatologist. 68. Ian.. 121 erythrocyte. 20. 92–93 Curie. Irene. 56 hematopoiesis. 48. Marie. 132 Hanseman. 80 Curie. 43 hematopoietic growth factors. 119 folate consumption. 84 Farber. 100 fertility issues. 116 FDA. 50 Enola Gay. 124 Fialkow. 8. 123 disease and leukemia risk. 70 immunosuppressive. 85 e Egypt. 13 differentiation therapy. 52 diet. 102–115 genetics and leukemia. 103–104 drug. See Mylotarg gender incidences. 123 diagnosis of leukemia. See also specific drugs development. 98–99 Fidler. 13 changes in. Vilhelm. 69 Harvard Medical School. 133 hemoglobin. See fluorescence in situ hybridization flow cytometry. Isaiah. 123 Frieben. 1236. 61. 114 bcr/abl gene. 42. 81. 6. 85. 24–25. 121 h hair loss. 21–22. 130–131. 62 Greeks. 84 electron microscope. 85. 121 Ehrlich. 52–53. 101 Gleevec (imatinib). 102–115 genome. 104 differentiation of cell types. 43 f Fallon. 103–104 DNA defects in. 92 cytogenetics. 114. John. 124 hairy cell leukemia. 8. 26 gemtuzumab ozogamicin. 99 Ellerman. 84. 25. Albert. 114. 132 bcr gene. 132–133 graft-versus-host disease. 81 Food and Drug Administration (FDA). 66. 130 heart problems. 38–41. 123 hematology. 57. 47–48 erythema dose. 90 d Delore. 119 fluorescence in situ hybridization (FISH). 94 dendritic cells. radiation. Ludwik. 118–120 Dick. 114 categories of. 43 external beam radiation. 132 granulocyte lineage. 8. 116. 79 fallout. 74 genes abl gene. 100 . 37 Gross. 37. 123 Fowler’s solution. 92–93 Curie. 97 “embryonic-like” cell. 76–77. 41. 66. 116.” 25 FISH. 89 eosinophil. Johannes. 16 Down syndrome. 18. 52 Fibiger. 68. 25. 124.14 index Craigie. Nevada. David von. 70. Pierre. 29. 82–83 fatigue. 109. 7. 57 exercise. Sidney A. 62–63 digestive system distress.

27 Hiroshima.index 15 herbicides. 77 lymphatic system. See incidence rates risk factors. 24 Lee. 80 induction therapy. 48 histology. 94 Lissauer. 97 Herceptin (trastuzumab). See genes. of leukemia treatment. 86 i imatinib. 6 HTLV-1. 58–59. 85 interferons. 118 lymphocytes. acute myelogenous leukemia. 60. 69. 58. 79–81 . 133 Hungerford. 19 Homo erectus. Heinrich. 43. 53 leukocytes. 47. 28–29. David. 133 J James I (king). 25. 95. Japan. 84. 55 leukapheresis. 77–81. 34 K Keller. 48. See Gleevec immunization. See also leeches histamines. 29. George. 11–12 Keller. 122 LSC. 45 immunophenotyping technique. 84 maintenance therapy. See diagnosis of leukemia gene changes. 74 infection. 71. changes in gender issues. See also specific types of leukemia leukemic stem cell (LSC). 50–52 lymph node. 48–52. 88–91 hirudin. David. childhood leukemia. changes in defined. 57. 27 Lane. 21 India. 76–77. See symptoms. 84. 64. 35–37 rates of. 21 intensification therapy. 60. John. 12 described. 41 lymphoma. See also acute lymphocytic leukemia. See chromosomes. 113 leukemia. 34 Hippocrates. 67. 133 Hill. 104. 8. 110–111. 97–101 inflammation. 38–39 l lancing. See tumor suppressor gene Innocent VII (pope). Tom. 25. 64. 102–115. 61. 117–118 leeches. See treatment types of. chronic myelogenous leukemia age of onset. 85 infant leukemia. 88. chronic lymphocytic leukemia. 73 Li-Fraumeni syndrome. See survival rates symptoms. 50. 79–81. 43–48 cancer of the blood. 49. 38–41. 37. Kathy. 64 blood cells and —. See human thymus-derived T-cell leukemia virus human thymus-derived T-cell leukemia virus (HTLV-1). 57. 84. 24 incidence rates. 52–53. See gender incidences history of. 72 m macrophage. 62. 54. 54–70. 11–13 Kochanowicz. 85 malignant tumor. 45–46. 109 Leakey. 88. 6. 103 Lignac. 133 survival rates. 101. 61. Louis. 28. 88–101 chromosomes changes. See leukemic stem cell lumbar puncture. 48 INK4. 15–19 causes of. 14 Manhattan Project. cause of leukemia. 99–100. 28 Hirudo medicinalis. 11–22 diagnosis of. Cammy. 27. 130 Incas. 62 magnetic fields. 88–101. 47 lymphoid stem cell. 89 maternal exposure to risk factors. Neil. 58 immunotherapy.

30–31 mucous membranes. 22 protein. 132 Roman empire. Arthur. 125 P Paget. 61 Philadelphia chromosome. 68 proto-oncogenes. 88. See National Cancer Institute Neumann. 132 Nowell. 60–61 radiation exposure to. 110 oxygen. 54 RSV. 93. 27 mutations of proto-oncogenes. 88. Steven A. 123 n Nagasaki. 14. 101. 129 natural killer cell (NK cell). See erythrocytes relapse. rates. Percival. 16. 47. 97. 90–91. 85. 25 red blood cells. 17. Ernest. 85. 132 Ramayana. 44 melanoma. 43 s sarcoma. Giovanni Battista. 97. 123 muscular tissues. 53 myeloma cell. 120. 24–25 receptor. 38. 124. 25 Rosenberg. 52 median age. 43 nausea. 101 p53. Richard. See Rous sarcoma virus Rutgers University. 87 retrovirus. 132 pernicious anemia. 116. Jim. 52 Mylotarg (gemtuzumab ozogamicin). 68–69 pancreas. 103 scrotal cancer. Peyton. 130 National Institutes of Health (NIH). 56–57 neural tissues. 14. 25 The Origin of Malignant Tumors (Boveri). 48. 83. 121. 90 nasopharyngeal cancer. 95. 110–113 nucleus. 13–14 rectum. cancer of. 39. 24 meningioma. 104 Rous sarcoma virus (RSV). 103 Pappenheim. 7 NK cell. 104. 118 o Ommaya reservoir. 107. 124 NCI. 62 Morgagni. 34 prognosis of leukemia. 132 myeloid stem cell. 118 megakaryocytes. 47 phenoxy. 39. See National Institutes of Health Nixon. See chromosomes. 34 . 71. 64 medical technologists. 7. 62. p53 phagocytic cell. Philadelphia chromosome placenta. 18 pentostatin. 41. 82 pesticides. 81. 107. 52–53 pluripotent stem cell. 86 metastasis. 77 National Marrow Donor Program. 64. 117 remission. 76. 43. 100 Revlimid. 38. See natural killer cell non-ablative allogenic stem cell transplantation. 7 National Cancer Institute (NCI). 53 Potts. 51 pathology. 73. 64. Ernst. 99 monocyte lineage. 104–106. 67. 13. 40 platelets. 25 National Cancer Act. 44–45. 22. 57 proliferation of blood cells. 117–118. 69. 71. 41. 115 oncogenic virus. 130–131 Rous. See tumor suppressor genes.1 index McCulloch. 58. 116. 41 NIH. 23. Stephen. 86 Schwachman-diamond syndrome. 124 oncogenes. 24. 97–98. Peter. electron. 115 psoriasis. Japan. 15 microscope. 104–105 Royal Infirmary (Scotland). 14 myelodysplastic syndrome. 130 plasma. 98 oncologist. 13 r race and leukemia. 34. 133 therapy.. 105. 41. 13–14. 52 McGriffin. 27 neutrophil. 84.

105 skin cancer. proto-oncogenes to oncogenes. 18 seed and soil hypothesis. cancer. 61. 19 University of Königsberg. 24. secondary cancer Sedgwick. 120–131 side effects. 87 v vaccine. 32–33 tyrosine kinase. 112 white blood cells. 76. 57 tretinoin. 20. George. 27 T lymphocytes. 27. 85–86. 114 turmeric. 106–108 INK4. See cancer. 124. See treatment tissues. 97 vomiting. 8 for childhood leukemia. 132 Velpeau. See leukocytes Wilms’ tumor. 32–33. 130 t therapeutic radiation. 108 p53. 85 w Waldeyer. 116. 112 University College London. 17–19. 62. 130 United States Naval Radiological Defense Laboratory. 80 typhus fever. 8 survival rates. 7. stem cells. 72–73 sun. 43 tobacco. 55. 81 trachea. 25 Sklodowska. 98–99 spleen. 62 transformation.” 101 Virchow. 125 “viral RNA. 132–133. 125–131. See smoking tonsils. side effect of treatment. Marie. chemotherapy. 23. See Curie. 50 topoisomerese II. therapy. 118 src (oncogene). See also leukemic stem cell transplantation. 14. 89 tumor. 37. 116. 33 University of Dundee. 64 therapy. 129 Uniformed Services University of Health Services. Wilhelm. 109 University of Edinburgh. 20–21 Wesleyan University. 83 World War II. overexposure to. 113 trastuzuma. 68 u umbilical cord. 98 signal molecules. 76. 92 Spiroptera carcinoma. 37. differentiation therapy. 105. 108. 38. 84–87 future. Marie smoking. 109. 85. 13. 71. 56 virus. 32–33 Washington. 87 of leukemia. 11. 102. 51. 134 stomach cancer. 8.index 1 Seats and Causes of Disease Investigated by Means of Anatomy (Morgagni). 35. radiation.. 34 . 120. 112 University of Washington. 13. 17. 68–69 Shope papilloma virus. transplantation for cancer. 76 transcription factor. 31 secondary cancer. 35 volatile solvents. transplant. 133 Sorbonne University. 11. 104–105 stem cells. 34. 86 tumor suppressor genes. 41. 25 Stroud. Alfred. See Vesanoid Trisenox. 31 University of Pennsylvania. 50. 88–90 x X-rays. 134 for leukemia. 13. See Herceptin treatment. 48. 109 University of Berlin. 82 Truman. Harry. Rudolf. 123 tropical anemia. 35 Vesanoid (tretinoin). 38. 64. See also bone marrow. Jennifer. 132. 107 translocation events. Mr. 74. 20–22 symptoms of childhood leukemia. 56–57 University of Padua.

She is the recipient of the Joanne Rathgeb Teaching Award from Saint Michael’s College. in biology from Manhattan College in 1978 and her M. genetics.A. Douglas Green. 1 . who is also a biology professor at Saint Michael’s. live in Vermont with their two teenage daughters. She and her husband.D. Bozzone earned her B. science writing. and a senior seminar on the history of biology. cell biology. An enthusiast for science education at all levels. and also works with students who are training to become biology teachers. She continued her education as a postdoctoral research associate at the Worcester Foundation for Experimental Biology. Bozzone designs laboratory teaching materials for students in high school and college. and Ph. Dr. developmental biology. Dr. An author of more than 25 publications.abouT The auThor ♦ donna m.S. Bozzone’s areas of specialization are in developmental and cellular biology. respectively. in biology from Princeton University in 1980 and 1983. Bozzone is also a member of the Publication Review Panel for the Journal of College Science Teaching and an ad hoc reviewer for American Biology Teacher. plant developmental physiology. She teaches or has taught courses in introductory biology. Dr. She joined the faculty of Saint Michael’s College in 1987 and is now Professor of Biology.