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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow / drug effects
  • Bone Marrow / metabolism
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disease Progression*
  • Humans
  • Inflammation Mediators / metabolism
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Interleukin-1 / metabolism*
  • Interleukin-1beta / blood
  • Interleukin-1beta / metabolism
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology*
  • Models, Biological
  • Monocytes / metabolism
  • Phosphorylation / drug effects
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction / drug effects
  • Tumor Stem Cell Assay
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Inflammation Mediators
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1
  • Interleukin-1beta
  • Receptors, Interleukin-1
  • p38 Mitogen-Activated Protein Kinases