Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

• 成果类型: Article
• 署名作者: Agarwal, Gaurav; Antoszewski, Mateusz; Xie, Xueqin; Pershad, Yash; Arora, Uma P.; Poon, Chi-Lam; Lyu, Peng; Lee, Andrew J.; Guo, Chun-Jie; Ye, Tianyi; Norford, Laila Barakat; Neehus, Anna-Lena; Della Volpe, Lucrezia; Wahlster, Lara; Ranasinghe, Diyanath; Ho, Tzu-Chieh; Barlowe, Trevor S.; Chow, Arthur; Schurer, Alexandra; Taggart, James; Durham, Benjamin H.; Abdel-Wahab, Omar; Mcgraw, Kathy L.; Allan, James M.; Soldatov, Ruslan; Bick, Alexander G.; Kharas, Michael G.; Sankaran, Vijay G.
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Howard Hughes Medical Institute; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Memorial Sloan Kettering Cancer Center; Vanderbilt University; Memorial Sloan Kettering Cancer Center; Harvard University; Harvard Medical School; Newcastle University - UK; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; Harvard University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adx4174
• 发表日期: 2026-01-01
• 页码: 52-58
• 关键词: genome-wide association; myeloid-leukemia; MSI2; screen; expression; reveals; loci; fate

摘要

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.