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

doi:10.1016/j.celrep.2017.03.018

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 journal › Article › peer-review

234 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 language	English (US)
Pages (from-to)	3204-3218
Number of pages	15
Journal	Cell Reports
Volume	18
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2017.03.018
State	Published - Mar 28 2017

Funding

This study was supported by NIH 5R00-CA151670-05 (A.A.), V Foundation Scholar (A.A.), and the Knight Cancer Institute Pilot Project (A.A.). B.J.D. is a Howard Hughes Medical Institute Investigator. J.W.T. is supported by NIH/NCI 5R01-CA183974-03. D.K.E. is supported by the NSF Graduate Research Fellowship (DGE-1448072). Primary samples are accessed through the Leukemia & Lymphoma Society SCOR 7005-11 and Beat AML program. The authors thank Dr. Marc Loriaux and Pierrette Lo for their critical review of the manuscript, Dorian LaTocha and Brianna Garcia for help with FACS experiments, and Sarah Bowden and Zoe Schmidt for administrative support.

Funders	Funder number
Knight Cancer Institute
Author National Science Foundation National Science Foundation National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health National Science Foundation National Science Foundation	DGE-1448072
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	5R00-CA151670-05
National Institute of Health-National Cancer Institute	R01CA178397, 5R01-CA183974-03
Leukemia and Lymphoma Society	SCOR 7005-11

Keywords

AML
IL1R1
bone marrow microenvironment
functional screening
interleukin-1
p38MAPK

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2017.03.018

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

Carey, A, Edwards, DK, Eide, CA, Newell, L , Traer, E, Medeiros, BC, Pollyea, DA, Deininger, MW, Collins, RH, Tyner, JW , Druker, BJ, Bagby, GC, McWeeney, SK & 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, vol. 18, no. 13, pp. 3204-3218. https://doi.org/10.1016/j.celrep.2017.03.018

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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.",

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AU - Medeiros, Bruno C.

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AU - Deininger, Michael W.

AU - Collins, Robert H.

AU - Tyner, Jeffrey W.

AU - Druker, Brian J.

AU - Bagby, Grover C.

AU - McWeeney, Shannon K.

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N2 - 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.

AB - 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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KW - interleukin-1

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

Abstract

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Keywords

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