SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition
Open accessAbstract
Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.
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HSCs from mice mutant for Sf3b1, Srsf2, and U2af1 have a competitive disadvantage in vivo, unlike the clonal expansion observed in humans with these mutations.
“HSCs from mice mutant for these genes, Sf3b1 56, Srsf2 57, and U2af1 58, have a competitive disadvantage in vivo, unlike the clonal expansion observed in humans with these mutations.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [57]
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- Authors
- Kim, E., Ilagan, J. O., Liang, Y., Daubner, G. M., Lee, S. C.-W., Ramakrishnan, A., Li, Y., Chung, Y. R., Micol, J.-B., Murphy, M. E., Cho, H., Kim, M.-K., Zebari, A. S., Aumann, S., Park, C. Y., Buonamici, S., Smith, P. G., Deeg, H. J., Lobry, C., Aifantis, I., Modis, Y., Allain, F. H.-T., Halene, S., Bradley, R. K., & Abdel-Wahab, O.
- Affiliations
- Fred Hutch Cancer Center (US)
- Yale Cancer Center (US)
- ETH Zurich (CH)
- Memorial Sloan Kettering Cancer Center (US)
- University of Washington (US)
- Yale University (US)
- Université Paris-Sud (FR)
- Howard Hughes Medical Institute (US)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Bradley, Robert K.
- Abdel-Wahab, Omar
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 27
- Issue
- 5
- Pages
- 617-630
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4429920
- OpenAlex
- W1506037097
- Cited by
- 575
- References
- 34
- Citations by year
- 2026: 42 · 2025: 42 · 2024: 44 · 2023: 55 · 2022: 48 · 2021: 60 · 2020: 59 · 2019: 59 · 2018: 61 · 2017: 43 · 2016: 45 · 2015: 15
- FWCI
- 23.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (acceptedVersion, cc-by-nc-nd)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Leukemia and Lymphoma Society
- Edward P. Evans Foundation
- Ed Evans Foundation
- National Institutes of Health
- Ellison Medical Foundation (AG-NS-1030-13, R56 DK103854)
- Damon Runyon Cancer Research Foundation (DFS 04-12)
- National Cancer Institute (P30 CA015704, P30 DK056465, T32 CA009657)
- National Institute of General Medical Sciences (101908/Z/13/Z, R01 GM102869)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK082783)
- Wellcome Trust
- U.S. Department of Defense
- Yale Cancer Center
- National Heart, Lung, and Blood Institute (U01 HL099993)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII3_127454)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- SRSF2, myelodysplastic syndrome, splicing factor mutations, exon recognition, exonic splicing enhancers, aberrant splicing, EZH2, nonsense-mediated mRNA decay, RNA binding, hematopoietic differentiation, hematopoiesis
- MeSH terms
- Serine-Arginine Splicing Factors, Enhancer of Zeste Homolog 2 Protein, Animals, Exons, Mice, Mutant Strains, Mutation, Myelodysplastic Syndromes, Nuclear Proteins, Ribonucleoproteins, RNA Splicing, Gene Expression, Mice, Proteolysis, Polycomb Repressive Complex 2
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