期刊
CANCER CELL
卷 27, 期 5, 页码 617-630出版社
CELL PRESS
DOI: 10.1016/j.ccell.2015.04.006
关键词
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资金
- Worldwide Cancer Research Fund
- NIH/NHLBI [U01 HL099993]
- NIH/NIDDK [K08 DK082783, R56 DK103854, P30 DK056465]
- J.P. McCarthy Foundation
- Storb Foundation
- Edward P. Evans Foundation
- Yale Comprehensive Cancer Center institutional funds
- Hartwell Innovation Fund
- Damon Runyon Cancer Research Foundation [DFS 04-12]
- Ellison Medical Foundation [AG-NS-1030-13]
- NIH/NCI [P30 CA015704, T32 CA009657]
- Fred Hutchinson Cancer Research Center institutional funds
- Leukemia and Lymphoma Society
- ATIP-Avenir grant from the French government
- NIH K08 clinical investigator award [1K08CA160647-01]
- Department of Defense Postdoctoral Fellow Award in Bone Marrow Failure Research [W81XWH-12-1-0041]
- Josie Robertson Investigator Program
- Damon Runyon Clinical Investigator Award
- Evans Foundation
- NCCR RNA and Disease - Swiss National Science Foundation
- SNF Sinergia [CRSII3_127454]
- NIH/NIGMS [R01 GM102869]
- Wellcome Trust [101908/Z/13/Z]
- Wellcome Trust [101908/Z/13/Z] Funding Source: Wellcome Trust
- Worldwide Cancer Research [15-0399] Funding Source: researchfish
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 missplicing 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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