JMG, SS1, Animals, Mice, Clonal Hematopoiesis, Receptors, Tumor Necrosis Factor, Type I, Tumor Necrosis Factor-alpha, Hematopoiesis, Hematopoietic Stem Cells, Cell Lineage
Cancer Discov. 2022;12(12):2763-73.
This work was sup- ported by NIH U01AG077925 (J.J. Trowbridge), NIH R01DK118072 (J.J. Trowbridge), NIH R01AG069010 (J.J. Trowbridge), and an Evans- MDS Discovery Research Grant (J.J. Trowbridge). This study was supported in part by The Jackson Laboratory’s Cancer Center Sup- port Grant NIH P30CA034196. L.S. Schwartz was supported by NIH F31DK127573. J.M. SanMiguel was supported by NIH T32AG062409, NIH T32HD007065, and an American Society of Hematology Scholar Award. J.J. Mistry was supported by a JAX Scholar award. G.A. Challen and J.J. Trowbridge are scholars of the Leukemia & Lymphoma Society. G.A. Challen was supported by NIH R01DK124883.
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.
Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness versus Lineage Output in Dnmt3a-Mutant Clonal Hematopoiesis. Cancer Discov. 2022;12(12):2763-73.