| Summary: | The myelodysplastic syndromes (MDS) are common myeloid malignancies. Mutations in splicing factor genes (including SF3B1, SRSF2 and U2AF1) occur in over half of MDS patients and result in aberrant pre-mRNA splicing of many target genes, indicating that aberrant spliceosome function plays a key role in the pathogenesis of MDS. However, the molecular mechanisms through which the splicing factor mutations drive the MDS phenotype are not fully understood. A previous study from our group has shown that the U2AF1S34F mutations induces aberrant splicing of STRAP in cells of the erythroid lineage. We have identified a splicing event of STRAP, identical to the one caused by the U2AF1S34F mutation, in the erythroid precursors of SRSF2 mutant MDS cases. Functional studies demonstrated that knockdown of STRAP leads to inactivation of p38 MAPK and downregulation of CSDE1-bound transcripts, suggesting that underlying mechanism of ineffective erythropoiesis in MDS with low expression of STRAP is caused by SRSF2 mutations. We have also performed an analysis on global splicing alteration using transcriptomic data of splicing factor mutant MDS patients, which revealed that splicing factor mutations (SF3B1 and SRSF2) reshape the mRNA splicing landscape in MDS. This analysis identified that alternative splicing is cell-type dependent and splicing factor mutations alter the pattern of whole mRNA splicing within each bone marrow subpopulation. SRSF2 is the most frequently mutated splicing factor gene with adverse prognosis in MDS. SRSF2 mutations commonly co-occur with mutations of other specific genes, most frequently TET2 and ASXL1. We performed single-cell transcriptomic analysis using the 10X Genomics platform on haematopoietic stem and progenitor cells of MDS patients harbouring SRSF2 mutations and co-mutations of TET2 and/or ASXL1. Cell population composition analysis revealed differences in population abundance across the genotype groups. Differential gene expression analysis unveiled genotype-specific gene expression signatures and dysregulated pathways.
|
|---|