2. Academic Validation
  3. Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

  • bioRxiv. 2025 Mar 26:2025.03.24.645017. doi: 10.1101/2025.03.24.645017.
Gaurav Agarwal 1 2 3 4,  Mateusz Antoszewski 1 2 3 4,  Xueqin Xie 5,  Yash Pershad 6,  Uma P Arora 1 2 3 4,  Chi-Lam Poon 7,  Peng Lyu 1 2 3 4,  Andrew J Lee 1 2 3 4,  Chun-Jie Guo 1 2 3 4,  Tianyi Ye 1 2 3 4,  Laila Barakat Norford 1 2 3 4,  Anna-Lena Neehus 1 2 3 4,  Lucrezia Della Volpe 1 2 3 4,  Lara Wahlster 1 2 3 4,  Diyanath Ranasinghe 8,  Tzu-Chieh Ho 5,  Trevor S Barlowe 5,  Arthur Chow 5,  Alexandra Schurer 5,  James Taggart 5,  Benjamin H Durham 5,  Omar Abdel-Wahab 5,  Kathy L McGraw 9,  James M Allan 8,  Ruslan Soldatov 7,  Alexander G Bick 6,  Michael G Kharas 5,  Vijay G Sankaran 1 2 3 4 10
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Howard Hughes Medical Institute, Boston, MA 02115, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 5 Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 7 Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • 9 Immune Deficiency Cellular Therapy Program, National Cancer Institute, National Institutes of Health, Bethesda, MD; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD; Myeloid Malignancies Program, National Institute of Health, Bethesda, MD.
  • 10 Harvard Stem Cell Institute, Cambridge, MA 02142, USA.
PMID: 40196615 DOI: 10.1101/2025.03.24.645017
Abstract

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.

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