Mutations in the Spliceosomal Gene ZRSR2 in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are characterized by recurrent somatic alterations often affecting components of RNA splicing machinery. Mutations of splice factors SF3B1, SRSF2, ZRSR2 and U2AF1 occur in greater than 50 percent of MDS. To assess the impact of spliceosome mutations on splicing and to identify common pathways/genes affected by distinct mutations, we performed RNA-sequencing of 32 MDS bone marrow samples harboring solely spliceosome mutations (including SF3B1, SRSF2 P95 or small deletions, U2AF1 S34 or Q157 hotspot mutations and ZRSR2 truncating alterations), but devoid of other co-occurring mutations. We uncover the landscape of splicing alterations in each splice factor mutant MDS and demonstrate that SRSF2 deletions cause highest number of splicing alterations compared with other spliceosome mutations. Although the mis-spliced events observed in different splice factor mutations were largely non-overlapping, a subset of genes, including EZH2, were aberrantly spliced in multiple mutant groups. Pathway analysis revealed dysregulated biological processes including RNA splicing and transport as well as several signaling cascades, which were observed repeatedly in different mutant groups, suggesting converging biological consequences downstream of distinct spliceosome mutations.