Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts
Open accessAbstract
BACKGROUND: Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODS: We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTS: We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONS: Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.).
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Patients with the ringed sideroblasts subtype of myelodysplastic syndrome carry a somatic mutation in the spliceosome gene SF3B1.
“Patients with the ringed sideroblasts subtype of myelodysplastic syndrome (once called refractory anemia with ringed sideroblasts) carry a somatic mutation in the spliceosome gene SF3B1.108”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [108]
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- Authors
- Papaemmanuil, E., Cazzola, M., Boultwood, J., Malcovati, L., Vyas, P., Bowen, D., Pellagatti, A., Wainscoat, J. S., Hellstrom-Lindberg, E., Gambacorti-Passerini, C., Godfrey, A. L., Rapado, I., Cvejic, A., Rance, R., McGee, C., Ellis, P., Mudie, L. J., Stephens, P. J., McLaren, S., Massie, C. E., Tarpey, P. S., Varela, I., Nik-Zainal, S., Davies, H. R., Shlien, A., Jones, D., Raine, K., Hinton, J., Butler, A. P., Teague, J. W., Baxter, E. J., Score, J., Galli, A., Della Porta, M. G., Travaglino, E., Groves, M., Tauro, S., Munshi, N. C., Anderson, K. C., El-Naggar, A., Fischer, A., Mustonen, V., Warren, A. J., Cross, N. C. P., Green, A. R., Futreal, P. A., Stratton, M. R., & Campbell, P. J.
- Affiliations
- Wellcome Sanger Institute (GB)
- Policlinico San Matteo Fondazione (IT)
- University of Oxford (GB)
- St James's University Hospital (GB)
- University of Milano-Bicocca (IT)
- University of Cambridge (GB)
- University of Southampton (GB)
- University of Dundee (GB)
- Harvard University (US)
- University of Cologne (DE)
- ORCID
- Papaemmanuil, E.
- Cazzola, M.
- Boultwood, J.
- Malcovati, L.
- Vyas, P.
- Bowen, D.
- Pellagatti, A.
- Gambacorti-Passerini, C.
- Godfrey, A.L.
- Cvejic, A.
- McLaren, S.
- Massie, C.E.
- Tarpey, P.S.
- Varela, I.
- Davies, H.R.
- Shlien, A.
- Jones, D.
- Raine, K.
- Hinton, J.
- Teague, J.W.
- Baxter, E.J.
- Travaglino, E.
- Tauro, S.
- Munshi, N.C.
- Anderson, K.C.
- Mustonen, V.
- Warren, A.J.
- Cross, N.C.P.
- Green, A.R.
- Futreal, P.A.
- Stratton, M.R.
- Campbell, P.J.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2011-10-13
- Volume
- 365
- Issue
- 15
- Pages
- 1384-1395
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3322589
- OpenAlex
- W2144892629
- Cited by
- 1,222
- References
- 7
- Citations by year
- 2026: 33 · 2025: 52 · 2024: 63 · 2023: 55 · 2022: 76 · 2021: 92 · 2020: 88 · 2019: 81 · 2018: 73 · 2017: 100 · 2016: 93 · 2015: 77 · 2014: 97 · 2013: 109 · 2012: 115
- FWCI
- 73.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (P50-100007)
- Adenoid Cystic Carcinoma Research Foundation
- Wellcome Trust (077012/Z/05/Z, 088340, 093867, WT088340MA)
- Università degli Studi di Milano
- National Institute for Health and Care Research
- Kay Kendall Leukaemia Fund
- Cancerfonden
- Fondazione Cariplo
- Universidad de Navarra
- Università degli Studi di Pavia
- Associazione Italiana per la Ricerca sul Cancro (WT088340MA)
- National Institutes of Health (P50-100007, 5p01ca078378-15)
- U.S. Public Health Service (P50-100007, P01-155249, P0178378, R01-124929)
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre
- National Cancer Institute (R01CA124929, P01-CA078378)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- SF3B1 mutation, myelodysplastic syndrome, ring sideroblasts, somatic point mutations, RNA splicing, mitochondrial pathway, cytopenia, event-free survival, somatic mutation frequency
- MeSH terms
- RNA Splicing Factors, Erythrocytes, Humans, Myelodysplastic Syndromes, Phenotype, Phosphoproteins, Point Mutation, Ribonucleoprotein, U2 Small Nuclear, Gene Expression Profiling, High-Throughput Nucleotide Sequencing
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