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, 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

Research output: Contribution to journalArticle

55 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3204-3218
Number of pages15
JournalCell Reports
Volume18
Issue number13
DOIs
StatePublished - Mar 28 2017

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia'. Together they form a unique fingerprint.

  • Cite this

    Carey, A., Edwards, D. K., Eide, C. A., Newell, L., Traer, E., Medeiros, B. C., Pollyea, D. A., Deininger, M. W., Collins, R. H., Tyner, J. W., Druker, B. J., Bagby, G. C., McWeeney, S. K., & Agarwal, A. (2017). Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia. Cell Reports, 18(13), 3204-3218. https://doi.org/10.1016/j.celrep.2017.03.018