Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.

Somatic mutations that increase hematopoietic stem cell (HSC) fitness drive their expansion in clonal hematopoiesis (CH) and predispose to blood cancers. Although CH frequently occurs with aging, it rarely progresses to overt malignancy. Population variation in the growth rate and potential of mutant clones suggests the presence of genetic factors protecting against CH, but these remain largely undefined. Here, we identify a non-coding regulatory variant, rs17834140-T, that significantly protects against CH and myeloid malignancies by downregulating HSC-selective expression and function of the RNA-binding protein MSI2. By modeling variant effects and mapping MSI2 binding targets, we uncover an RNA network that maintains human HSCs and influences CH risk. Importantly, rs17834140-T is associated with slower CH expansion rates in humans, and stem cell MSI2 levels modify ASXL1-mutant HSC clonal dominance in experimental models. These findings leverage natural resilience to highlight a key role for post-transcriptional regulation in human HSCs, and offer genetic evidence supporting inhibition of MSI2 or its downstream targets as rational strategies for blood cancer prevention.