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Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs
Open accessAbstract
Despite evidence of chronic inflammation in myelodysplastic syndrome (MDS) and cell-intrinsic dysregulation of Toll-like receptor (TLR) signaling in MDS hematopoietic stem and progenitor cells (HSPCs), the mechanisms responsible for the competitive advantage of MDS HSPCs in an inflammatory milieu over normal HSPCs remain poorly defined. Here, we found that chronic inflammation was a determinant for the competitive advantage of MDS HSPCs and for disease progression. The cell-intrinsic response of MDS HSPCs, which involves signaling through the noncanonical NF-κB pathway, protected these cells from chronic inflammation as compared to normal HSPCs. In response to inflammation, MDS HSPCs switched from canonical to noncanonical NF-κB signaling, a process that was dependent on TLR-TRAF6-mediated activation of A20. The competitive advantage of TLR-TRAF6-primed HSPCs could be restored by deletion of A20 or inhibition of the noncanonical NF-κB pathway. These findings uncover the mechanistic basis for the clonal dominance of MDS HSPCs and indicate that interfering with noncanonical NF-κB signaling could prevent MDS progression.
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“and exhibit a toll-like receptor–TNF receptor associated factor 6A (TLR-TRAF6A) and noncanonical NF-κB–dependent competitive advantage during low-grade inflammation.17”
From Aging drives Tet2 +/− clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [17]
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Metadata
- Authors
- Muto, T., Walker, C. S., Choi, K., Hueneman, K., Smith, M. A., Gul, Z., Garcia-Manero, G., Ma, A., Zheng, Y., & Starczynowski, D. T.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- University of Cincinnati (US)
- University of California, San Francisco (US)
- Corresponding author
- Starczynowski, Daniel T.
- ORCID
- Venue
- Nature Immunology
- Published
- 2020-04-20
- Volume
- 21
- Issue
- 5
- Pages
- 535-545
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC7402480
- OpenAlex
- W3017327186
- Cited by
- 155
- References
- 59
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 30 · 2023: 24 · 2022: 24 · 2021: 28 · 2020: 16
- FWCI
- 14.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R35HL135787)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102759, R01DK113639)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- myelodysplastic syndrome, hematopoietic stem and progenitor cells, chronic inflammation, non-canonical NF-κB signaling, Toll-like receptor signaling, TRAF6, A20, clonal dominance, myelopoiesis, disease progression, competitive advantage
- MeSH terms
- Tumor Necrosis Factor alpha-Induced Protein 3, Aged, Animals, Cell Differentiation, Cells, Cultured, Hematopoietic Stem Cells, Humans, Inflammation, Male, Mice, Transgenic, Myelodysplastic Syndromes, Signal Transduction, NF-kappa B, Myelopoiesis, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Mice
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