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

Clonal hematopoiesis resulting from the enhanced fi tness 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 TNF alpha signaling promoted the selective advantage of mutant HSCs and stimulated the production of mutant B lymphoid cells. The genetic loss of the TNF alpha 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.

Automated summary

Clonal hematopoiesis resulting from enhanced fitness of mutant hematopoietic stem cells can lead to both favorable and unfavorable health outcomes. This study found that aging-induced TNF alpha signaling promotes the selective advantage of mutant HSCs and stimulates the production of mutant B lymphoid cells. The loss of TNFR1 abolishes the advantage of mutant HSCs, while the loss of TNFR2 results in overproduction of mutant myeloid cells without affecting HSC fitness.