| Literature DB >> 25965569 |
Eunhee Kim1, Janine O Ilagan2, Yang Liang3, Gerrit M Daubner4, Stanley C-W Lee1, Aravind Ramakrishnan5, Yue Li6, Young Rock Chung1, Jean-Baptiste Micol1, Michele E Murphy7, Hana Cho1, Min-Kyung Kim1, Ahmad S Zebari2, Shlomzion Aumann1, Christopher Y Park8, Silvia Buonamici9, Peter G Smith9, H Joachim Deeg5, Camille Lobry10, Iannis Aifantis11, Yorgo Modis12, Frederic H-T Allain4, Stephanie Halene3, Robert K Bradley13, Omar Abdel-Wahab14.
Abstract
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 mis-splicing 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.Entities:
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Year: 2015 PMID： 25965569 PMCID： PMC4429920 DOI： 10.1016/j.ccell.2015.04.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743