SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition Academic Article uri icon


MeSH Major

  • Exons
  • Mutation
  • Myelodysplastic Syndromes
  • Nuclear Proteins
  • Ribonucleoproteins


  • 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.

publication date

  • January 2015



  • Academic Article



  • eng

PubMed Central ID

  • PMC4429920

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2015.04.006

PubMed ID

  • 25965569

Additional Document Info

start page

  • 617

end page

  • 30


  • 27


  • 5