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Cell Rep. 2017 Mar 28;18(13):3204-3218. doi: 10.1016/j.celrep.2017.03.018.

Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia.

Author information

1
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
2
Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
3
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA; Howard Hughes Medical Institute, Portland, OR 97239, USA.
4
Stanford University School of Medicine, Stanford, CA 94305, USA.
5
University of Colorado School of Medicine, Aurora, CO 80045, USA.
6
University of Utah Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
7
University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8
Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
9
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: agarwala@ohsu.edu.

Abstract

Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ∼67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.

KEYWORDS:

AML; IL1R1; bone marrow microenvironment; functional screening; interleukin-1; p38MAPK

PMID:
28355571
PMCID:
PMC5437102
DOI:
10.1016/j.celrep.2017.03.018
[Indexed for MEDLINE]
Free PMC Article

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