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

Autor:	Carey A; Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA., Edwards DK 5th; Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA., Eide CA; 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., Newell L; Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA., Traer E; Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA., Medeiros BC; Stanford University School of Medicine, Stanford, CA 94305, USA., Pollyea DA; University of Colorado School of Medicine, Aurora, CO 80045, USA., Deininger MW; University of Utah Huntsman Cancer Institute, Salt Lake City, UT 84112, USA., Collins RH; University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Tyner JW; Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA., Druker BJ; 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., Bagby GC; Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA., McWeeney SK; Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA., Agarwal A; 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.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2017 Mar 28; Vol. 18 (13), pp. 3204-3218.
DOI:	10.1016/j.celrep.2017.03.018
Abstrakt:	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. (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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