| First Author | SanMiguel JM | Year | 2022 |
| Journal | Cancer Discov | Volume | 12 |
| Issue | 12 | Pages | 2763-2773 |
| PubMed ID | 36169447 | Mgi Jnum | J:347574 |
| Mgi Id | MGI:7397318 | Doi | 10.1158/2159-8290.CD-22-0086 |
| Citation | SanMiguel JM, et al. (2022) Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness versus Lineage Output in Dnmt3a-Mutant Clonal Hematopoiesis. Cancer Discov 12(12):2763-2773 |
| abstractText | 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 TNFalpha signaling promoted the selective advantage of mutant HSCs and stimulated the production of mutant B lymphoid cells. The genetic loss of the TNFalpha 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 TNFalpha 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 Nino and Pietras, p. 2724. This article is highlighted in the In This Issue feature, p. 2711. |
