GSE203550
Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness Versus Lineage Output in Murine Dnmt3a-Mutant Clonal Hematopoiesis
Clonal hematopoiesis resulting from enhanced fitness of mutant hematopoietic stem cells (HSCs) 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 DNMT3AR882/+ clonal hematopoiesis (Dnmt3aR878H/+), we found that aging-induced TNFa signaling promoted the selective advantage of mutant HSCs as well as stimulated mutant B lymphoid cell production. Genetic loss of TNFa receptor TNFR1 impaired mutant HSC fitness without altering lineage output, while loss of TNFR2 reduced lymphoid cell production and favored myeloid cell production from mutant HSCs without altering overall fitness. These results support a model where clone size and mature blood lineage production can be independently controlled to harness potential beneficial aspects of clonal hematopoiesis. Overall design: 1x10^6 CD45.2+ cells were competed against 1x10^6 CD45.1+ post-ficoll whole BM cells and transplanted into aged, lethally irradiated CD45.1+ recipient animals. One month post-transplant, the recipients received one IP injection of poly(I:C) and recombination was checked via PCR on PB. One month post poly(I:C), animals were bled monthly for 16 weeks. Bone marrow was harvested and 4x10^6 post-ficoll whole BM cells were used for secondary transplantation into aged, lethally irradiated recipients. Recipients were harvested 20 weeks post-transplant.