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

Publication date: 28 March 2017
Source:Cell Reports, Volume 18, Issue 13
Author(s): 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
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.

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Carey et al. show that most AML patients are dependent on IL-1 and suggest that an IL-1-rich environment promotes the expansion of AML progenitors while suppressing normal progenitors by differently influencing cell proliferation, survival, and differentiation. AML patients with aberrant IL-1 signaling may benefit from therapeutically targeting this pathway to enhance normal hematopoiesis while inhibiting AML.


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