Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness versus Lineage Output in Dnmt3a-Mutant Clonal Hematopoiesis

SanMiguel, Jennifer M., Eudy, Elizabeth, Loberg, Matthew A., Young, Kira A., Mistry, Jayna J., Mujica, Kristina D., Schwartz, Logan S., Stearns, Timothy M., Challen, Grant A. and Trowbridge, Jennifer J. (2022) Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness versus Lineage Output in Dnmt3a-Mutant Clonal Hematopoiesis. Cancer Discovery, 12 (12). pp. 2763-2773. ISSN 2159-8274

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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 regu-lated 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.

Item Type:	Article
Additional Information:	Data Availability Statement: All data in this study are deposited in the NCBI Gene Expression Omnibus (RRID:SCR_005012) under accession numbers GSE189406 (bulk RNA-seq) and GSE203550 (single-cell RNA-seq).
Uncontrolled Keywords:	oncology,das in place,data availability statement all data in this study are deposited in the ncbi gene expression omnibus (rrid:scr_005012) under accession numbers gse189406 (bulk rna-seq) and gse203550 (single-cell rna-seq).,2026 ,/dk/atira/pure/subjectarea/asjc/2700/2730
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	10 Nov 2026 16:26
Last Modified:	10 Nov 2026 16:26
URI:	https://ueaeprints.uea.ac.uk/id/eprint/105048
DOI:	10.1158/2159-8290.CD-22-0086

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