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Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo
Open accessAbstract
Heterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼ 11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq). Integration with human RNA-seq datasets determined that common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and recurrently mutated MDS and acute myeloid leukemia-associated genes. These findings support the hypothesis that mutant U2AF1 alters downstream gene isoform expression, thereby contributing to abnormal hematopoiesis in patients with MDS.
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“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 [58]
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Metadata
- Authors
- Shirai, C. L., Ley, J. N., White, B. S., Kim, S., Tibbitts, J., Shao, J., Ndonwi, M., Wadugu, B., Duncavage, E. J., Okeyo-Owuor, T., Liu, T., Griffith, M., McGrath, S., Magrini, V., Fulton, R. S., Fronick, C., O’Laughlin, M., Graubert, T. A., & Walter, M. J.
- Affiliations
- Washington University in St. Louis (US)
- Harvard University (US)
- Corresponding author
- Walter, Matthew J.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 27
- Issue
- 5
- Pages
- 631-643
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4430854
- OpenAlex
- W1536775300
- Cited by
- 287
- References
- 54
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 18 · 2023: 30 · 2022: 20 · 2021: 30 · 2020: 32 · 2019: 33 · 2018: 24 · 2017: 26 · 2016: 32 · 2015: 13
- FWCI
- 13.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000448)
- National Heart, Lung, and Blood Institute (K12HL087107, T32HL007088)
- National Cancer Institute (T32CA113275, P50CA171963, P30CA091842, K12CA167540)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- U2AF1, myelodysplastic syndrome, pre-mRNA splicing, hematopoiesis, hematopoietic progenitor cells, spliceosome, acute myeloid leukemia, ribosomal genes, RNA processing genes
- MeSH terms
- Splicing Factor U2AF, Animals, Hematopoiesis, Humans, Mice, Transgenic, Mutation, Myelodysplastic Syndromes, Nuclear Proteins, Ribonucleoproteins, RNA Precursors, RNA Splicing, RNA, Messenger, Leukemia, Myeloid, Acute
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