Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

Somatic mutations increasing hematopoietic stem cell (HSC) fitness drive their expansion in clonal hematopoiesis (CH) and predispose to blood cancers. Population variation in the growth rate and potential of mutant clones suggests genetic factors may confer resilience against CH. Here, we identified a non-coding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively downregulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified ASXL1-mutant HSC clonal dominance. These findings leverage natural resilience to illuminate post-transcriptional regulation in human HSCs, suggesting inhibition of MSI2 or its targets for blood cancer prevention.