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Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness versus Lineage Output in Dnmt3a -Mutant Clonal Hematopoiesis
Published version of a preprint
Abstract
Clonal hematopoiesis resulting from the enhanced fitness of mutant hematopoietic stem cells (HSC) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of a clonal hematopoiesis–associated mutation, DNMT3AR882/+ (Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs and stimulated the production of mutant B lymphoid cells. The genetic loss of the TNFα receptor TNFR1 ablated the selective advantage of mutant HSCs without altering their lineage output, whereas the loss of TNFR2 resulted in the overproduction of mutant myeloid cells without altering HSC fitness. These results nominate TNFR1 as a target to reduce clonal hematopoiesis and the risk of associated diseases and support a model in which clone size and mature blood lineage production can be independently controlled to modulate favorable and unfavorable clonal hematopoiesis outcomes. Significance: Through the identification and dissection of TNFα signaling as a key driver of murine Dnmt3a-mutant hematopoiesis, we report the discovery that clone size and production of specific mature blood cell types can be independently regulated. See related commentary by Niño and Pietras, p. 2724. This article is highlighted in the In This Issue feature, p. 2711
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“While we provide a hypothesis for clonal selection in human CH, functional experiments are required to define those pathways causative of clonal expansion, although prior functional murine studies support our findings.32,45,46,47,49,97”
From Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging (2024) · cites this paper as [46]
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“Prior murine studies show that Tet2−/−, Dnmt3a−/−, and Dnmt3aR878H/+ HSPCs exhibit clonal advantage in inflammatory environments.45,46,47,48,49,50,97”
From Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging (2024) · cites this paper as [46]
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“Notably, infection and inflammation increase clonal advantage of Dnmt3a−/−, Tet2−/−, and Tet2+/− HSCs, which is abrogated by deletion of several cytokine receptors.45,46,47,48,49,50”
From Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging (2024) · cites this paper as [46]
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Cited by
Jakobsen, N. A., Turkalj, S., Zeng, A. G. X., Stoilova, B., Metzner, M., Rahmig, S., Nagree, M. S., Shah, S., Moore, R., Usukhbayar, B., et al. (2024) · Cell Stem Cell · doi:10.1016/j.stem.2024.05.010 · Cited by 130
Bone marrow inflammation in haematological malignancies
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Metadata
- Authors
- SanMiguel, J. M., Eudy, E., Loberg, M. A., Young, K. A., Mistry, J. J., Mujica, K. D., Schwartz, L. S., Stearns, T. M., Challen, G. A., & Trowbridge, J. J.
- Affiliations
- 1The Jackson Laboratory, Bar Harbor, Maine.
- 3Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2022-09-28
- Volume
- 12
- Issue
- 12
- Pages
- 2763-2773
- ISSN
- 2159-8274
- 2159-8290
- PMC
- PMC9716249
- Cited by
- 97
- References
- 10
- Language
- en
- Funders
- National Institute on Aging (U01AG077925, R01AG069010, T32AG062409)
- Division of Diabetes, Endocrinology, and Metabolic Diseases (R01DK118072, R01DK124883, F31DK127573)
- National Cancer Institute (P30CA034196)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007065)
- Edward P. Evans Foundation
- American Society of Hematology
- Leukemia and Lymphoma Society
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