Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia
Alyssa Carey,
David K. Edwards, V,
Christopher A. Eide,
Laura Newell,
Elie Traer,
Bruno C. Medeiros,
Daniel A. Pollyea,
Michael W. Deininger,
Robert H. Collins,
Jeffrey W. Tyner,
Brian J. Druker,
Grover C. Bagby,
Shannon K. McWeeney,
Anupriya Agarwal
Affiliations
Alyssa Carey
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
David K. Edwards, V
Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Christopher A. Eide
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Laura Newell
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Elie Traer
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Bruno C. Medeiros
Stanford University School of Medicine, Stanford, CA 94305, USA
Daniel A. Pollyea
University of Colorado School of Medicine, Aurora, CO 80045, USA
Michael W. Deininger
University of Utah Huntsman Cancer Institute, Salt Lake City, UT 84112, USA
Robert H. Collins
University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jeffrey W. Tyner
Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Brian J. Druker
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Grover C. Bagby
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Shannon K. McWeeney
Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Anupriya Agarwal
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
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.
