Aberrant activation of TCL1A promotes stem cell expansion in clonal hematopoiesis

Mutations in a diverse set of driver genes increase fitness of hematopoietic stem cells (HSCs), leading to outgrowths termed ‘clonal hematopoiesis’ (CH) 1 . These lesions are precursors for blood cancers 2 - 6 , but the reasons for their fitness advantage remain largely unknown, partially due to a paucity of cohorts where clonal expansion rate has been assessed by longitudinal sampling. To circumvent this limitation, we developed a method to infer expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate) and applied it to 5,071 persons with CH. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter associated with slower expansion rate in CH overall, but the effect varied by driver gene. Those carrying this protective allele had markedly reduced growth rate or prevalence of clones with driver mutations in TET2 , ASXL1 , SF3B1 , and SRSF2 , but not DNMT3A . TCL1A was not expressed in normal or DNMT3A -mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to TCL1A protein expression and expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did TCL1A shRNA knockdown. Forced expression of TCL1A promoted expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal hematopoiesis may be mediated by TCL1A activation.