SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition

•Srsf2P95H/wild-type mice develop myelodysplasia but Srsf2-deficient mice do not•Proline 95 mutations change the RNA binding specificity of SRSF2•Mutant SRSF2 promotes an isoform of EZH2 that undergoes nonsense-mediated decay•Restoring EZH2 expression partially rescues hematopoiesis in Srsf2 mutant cells

SummaryMutations 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.

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