Splicing is an essential cellular process which is carried out by the spliceosome in
order to remove the introns and join the exons present in pre-mRNA transcripts. A variety of
spliceosomal mutations have been recently identified in the myelodysplastic syndromes (MDS), a
heterogeneous group of hematopoietic stem cell malignancies, revealing a new leukemogenic
pathway involving spliceosomal dysfunction. Splicing factor genes are the most frequently mutated
genes found in MDS, with mutations occurring in more than half of all patients. The high
mutation frequency in different components of the spliceosome in MDS indicates that aberrant
splicing may be a common consequence of these mutations in this disorder. RNA sequencing
studies using MDS patient bone marrow cells and different mouse models have identified several downstream targets of the splicing factor
mutations. Aberrant splicing of these target genes may contribute to MDS pathogenesis, however functional studies are required in
order to fully determine the effects of the aberrant isoforms on disease phenotype. Splicing inhibitors are currently being developed and
may be used as therapeutic agents to target aberrant pre-mRNA splicing in MDS and other cancers with splicing factor mutations. The
mouse models expressing splicing factor mutations may prove particularly valuable for pre-clinical testing of these drugs.
Keywords: Myelodysplastic syndromes, splicing factor gene, mutations, RNA splicing, SF3B1, SRSF2, U2AF1, ZRSR2.
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