Cited by 287RNA Research and SplicingAcute Myeloid Leukemia ResearchRetinoids in leukemia and cellular processes

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Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo

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Shirai, Cara Lunn, Ley, James N., White, Brian S., Kim, Sanghyun, Tibbitts, Justin, Shao, Jin, Ndonwi, Matthew, Wadugu, Brian, Duncavage, Eric J., Okeyo-Owuor, Theresa, Liu, Tuoen, Griffith, Malachi, McGrath, Sean, Magrini, Vincent, Fulton, Robert S., Fronick, Catrina, O’Laughlin, Michelle, Graubert, Timothy A., Walter, Matthew J.·2015·Cancer Cell

DOI 10.1016/j.ccell.2015.04.008PMC PMC4430854

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Abstract

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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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: Shirai, Cara Lunn
White, Brian S.
Kim, Sanghyun
Shao, Jin
Wadugu, Brian
Duncavage, Eric J.
Liu, Tuoen
Griffith, Malachi
McGrath, Sean
Magrini, Vincent
Fulton, Robert S.
Fronick, Catrina
O’Laughlin, Michelle
Graubert, Timothy A.
Walter, Matthew J.
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2015-05
Volume: 27
Issue: 5
Pages: 631-643
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2015.04.008
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 376 d)
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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Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo

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