title: Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia.
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.
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Carey
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Edwards
authors.affiliation: 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.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Newell
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Elie
authors.initials: E
authors.lastname: Traer
authors.affiliation: Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pollyea
authors.affiliation: University of Utah Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Collins
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: 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.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
authors.affiliation: Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McWeeney
authors.affiliation: 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.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
mesh_terms: D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: AML; IL1R1; bone marrow microenvironment; functional screening; interleukin-1; p38MAPK