Identification of interleukin-1 by functional screening as a key mediator of cellular expansion and disease progression in acute myeloid leukemia
Open accessAbstract
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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Hematological malignancies that frequently carry TET2 founding mutations, such as MDS and AML, display dependencies on IL-1 signaling.
“hematological malignancies that frequently carry TET2 founding mutations, such as MDS and AML, display dependencies on IL-1 signaling.53, 54, 55”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [55]
The Results section ('Absence of IL-1 receptor attenuates the expansion of AML cells in vitro and disease progression in vivo'; page unavailable) reports that IL-1-sensitive AML samples depended on IL-1 receptors for survival. The paper does not establish an IL-1-signaling dependency in MDS or link that dependency to TET2 founding mutations; its AML finding is limited to a subset of samples. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBlockade of these pathways can limit and/or reverse disease progression.
“blockade of these pathways can limit and/or reverse disease progression (Carey et al., 2017; Mitchell et al., 2018; Rhyasen et al., 2013; Zhang et al., 2016)”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Carey et al., 2017
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- Authors
- 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.
- Affiliations
- Oregon Health & Science University (US)
- Howard Hughes Medical Institute (US)
- Stanford Medicine (US)
- University of Colorado Anschutz (US)
- University of Utah (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Agarwal, Anupriya
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 18
- Issue
- 13
- Pages
- 3204-3218
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5437102
- OpenAlex
- W2597865830
- Cited by
- 270
- References
- 50
- Citations by year
- 2026: 22 · 2025: 33 · 2024: 37 · 2023: 27 · 2022: 41 · 2021: 36 · 2020: 28 · 2019: 21 · 2018: 20 · 2017: 5
- FWCI
- 15.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH (5R00-CA151670-05)
- V Foundation Scholar
- Knight Cancer Institute Pilot Project
- NIH/NCI (5, R01-CA, 183974-03)
- NSF Graduate Research Fellowship (DGE-1448072)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- interleukin-1, acute myeloid leukemia, IL-1 receptor 1, p38 MAPK signaling, leukemia cell proliferation, disease progression, functional screening, targeted therapy
- MeSH terms
- Bone Marrow, Cell Survival, Humans, Interleukin-1, Models, Biological, Monocytes, Phosphorylation, Tumor Stem Cell Assay, Signal Transduction, Leukemia, Myeloid, Acute, Receptors, Interleukin-1, Disease Progression, Inflammation Mediators, Intercellular Signaling Peptides and Proteins, p38 Mitogen-Activated Protein Kinases, Cell Proliferation, Interleukin-1beta
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