Distinct TNF Receptors Dictate Stem Cell Fitness Versus Lineage Output in Clonal Hematopoiesis of Aging

Clonal hematopoiesis of aging results from enhanced fitness of mutant hematopoietic stem cells (HSCs) and associates with both favorable and unfavorable health outcomes related to lineage cell types produced by mutant HSCs. The extent to which lineage output can be controlled in clonal hematopoiesis is unknown. Using a mouse model of DNMT3AR882/+ clonal hematopoiesis (Dnmt3aR878H/+), we find that aging-induced TNFα signaling drives selective advantage of mutant HSCs concomitant with B lymphoid lineage production. Genetic loss of TNFα receptor TNFR1 impaired mutant HSC fitness while loss of TNFR2 abrogated lymphoid production and resulted in unrestrained myeloid cell production from mutant HSCs. These results support a model where clone size and lineage output can be independently targeted to harness potential beneficial aspects of clonal hematopoiesis. Mx1-Cre (control) or Dnmt3a-mutant (D3a-mut) bone marrow from young donors was tranplanted into young or aged recipient CD45.1 mice. 4 months post-transplant, LT-HSCs or MPP3s were re-isolated from the recipients and submitted for RNA-seq analysis. Aged Control LT-HSCs (n = 3), Aged Control MPP3s (n = 4), Aged D3Amut LT-HSCs (n = 4), aged D3Amut MPP3s (n=4), young control LT-HSCs (n = 4), young control MPP3s (n =4), young D3Amut LTHSCs (n =2), young D3amut MPP3s (n = 3)