Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation
Menée à partir de données de la "UK biobank", de l'étude "Geisinger Health" et de cohortes américaines portant au total sur 598 761 témoins et 43 619 patients avec hématopoïèse clonale de potentiel indéterminé, cette étude identifie un variant régulateur non codant (rs17834140-T) qui protège contre l'hématopoïèse clonale et les cancers myéloïdes en réduisant de manière sélective le niveau d'expression de la protéine de liaison à l'ARN musashi 2 (MSI2) dans les cellules souches hématopoïétiques
Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating 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. Variant 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 posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention. As people age, they often develop clonal hematopoiesis, or accumulation of blood cells with specific mutations that offer a survival advantage to those cells but not to the entire organism. Not all patients with clonal hematopoiesis develop clinical manifestations, but it does increase the long-term risk of illness, most notably cardiovascular disease and some blood cancers. By analyzing data from tens of thousands of patients and hundreds of thousands of controls across multiple studies, Agarwal et al. identified and studied the mechanism of a genetic variant that has the opposite effect, slowing down the expansion of clonal hematopoiesis and decreasing the risk of malignancy (see the Perspective by Caiado and Manz). —Yevgeniya Nusinovich
Science , résumé, 2026