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Lookup NU author(s): Dean Ranasinghe, Professor James AllanORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Agarwal G, Antoszewski M, Xie X, Pershad Y, Arora UP, Poon C-L, Lyu P, Lee AJ, Guo C-J, Ye T, Norford LB, Neehus A-L, della Volpe L, Wahlster L, Ranasinghe D, Ho T-C, Barlowe T-S, Chow A, Schurer A, Taggart J, Durham BH, Abdel-Wahab O, McGraw KL, Allan JM, Soldatov R, Bick AG, Kharas MG, Sankaran VG
Publication type: Article
Publication status: Published
Journal: Science
Year: 2026
Volume: 391
Issue: 6780
Pages: 52-58
Print publication date: 01/01/2026
Online publication date: 01/01/2026
Acceptance date: 27/10/2025
Date deposited: 17/12/2025
ISSN (print): 0036-8075
ISSN (electronic): 1095-9203
Publisher: American Association for the Advancement of Science
URL: https://doi.org/10.1126/science.adx4174
DOI: 10.1126/science.adx4174
ePrints DOI: 10.57711/01p1-e344
Data Access Statement: All raw data for CD34+ MSI2-HyperTRIBE are available from the European Nucleotide Archive (ENA) under study accession no. ERP182264. All raw data for scRNA-seq (GSE291294) and related code are available in our GitHub repository (https://github.com/sankaranlab/chip_resilience) and Zenodo (67). Bulk RNA-seq (GSE291293) experiments are available in the Gene Expression Omnibus (GEO) repository. Bulk RNA-seq data of ASXL1 mutant or wild-type CD34+ cells from chronic myelomonocytic leukemia patients (GSE159543) were previously reported (48). No original code or materials were generated in this study.
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