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Frequent pathway mutations of splicing machinery in myelodysplasia
Abstract
Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (∼45 to ∼85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.
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“mutations in several components of the core splicing apparatus, such as U2 small nuclear ribonucleoprotein auxiliary factor 2 (U2AF65), splicing factor 3B, subunit 1 (SF3B1) and other proteins, were found to cause very specific splicing defects in particular transcripts and to lead to a highly tissue-specific phenotype185–187.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [185]
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Metadata
- Authors
- Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R., Sato, Y., Sato-Otsubo, A., Kon, A., Nagasaki, M., Chalkidis, G., Suzuki, Y., Shiosaka, M., Kawahata, R., Yamaguchi, T., Otsu, M., Obara, N., Sakata-Yanagimoto, M., Ishiyama, K., Mori, H., Nolte, F., Hofmann, W.-K., Miyawaki, S., Sugano, S., Haferlach, C., Koeffler, H. P., Shih, L.-Y., Haferlach, T., Chiba, S., Nakauchi, H., Miyano, S., & Ogawa, S.
- Affiliations
- The University of Tokyo (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Heidelberg University (DE)
- Japan Science and Technology Agency (JP)
- University of Tsukuba (JP)
- Tokyo Metropolitan Ohtsuka Hospital (JP)
- SHOWA Medical University Fujigaoka Hospital (JP)
- Munich Leukemia Laboratory (Germany) (DE)
- Cedars-Sinai Medical Center (US)
- Chang Gung University (TW)
- Corresponding author
- Ogawa, Seishi
- ORCID
- Yoshida, Kenichi
- Sanada, Masashi
- Shiraishi, Yuichi
- Nowak, Daniel
- Nagata, Yasunobu
- Sato, Yusuke
- Kon, Ayana
- Nagasaki, Masao
- Suzuki, Yutaka
- Yamaguchi, Tomoyuki
- Otsu, Makoto
- Obara, Naoshi
- Ishiyama, Ken
- Nolte, Florian
- Miyawaki, Shuichi
- Sugano, Sumio
- Haferlach, Claudia
- Koeffler, H. Phillip
- Shih, Lee-Yung
- Haferlach, Torsten
- Chiba, Shigeru
- Nakauchi, Hiromitsu
- Miyano, Satoru
- Ogawa, Seishi
- Venue
- Nature
- Published
- 2011-09-11
- Volume
- 478
- Issue
- 7367
- Pages
- 64-69
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2073889874
- Cited by
- 2,029
- References
- 37
- Citations by year
- 2026: 71 · 2025: 76 · 2024: 121 · 2023: 101 · 2022: 139 · 2021: 160 · 2020: 148 · 2019: 135 · 2018: 135 · 2017: 148 · 2016: 146 · 2015: 145 · 2014: 173 · 2013: 171 · 2012: 135
- FWCI
- 64.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (22390191, 23791075, 22790895, 23659533, 23659482, 23390269, 23791068, 22659058)
- National Cancer Institute (R01CA026038)
- 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 › Genetics › Genomics and Rare Diseases
- Keywords
- myelodysplastic syndrome, splicing mutation, U2AF35, ZRSR2, SRSF2, SF3B1, 3' splice site recognition, pre-mRNA splicing, hematopoiesis, acute myeloid leukemia, myeloid neoplasms, aberrant splicing, therapeutic target
- MeSH terms
- Splicing Factor U2AF, Hematopoiesis, Humans, Mutation, Myelodysplastic Syndromes, Nuclear Proteins, Ribonucleoproteins, RNA Splicing, Spliceosomes, Alternative Splicing, Polymorphism, Single Nucleotide, RNA Splice Sites, Exome
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