Targeting Aberrant Splicing in Myelodysplastic Syndromes: Biologic Rationale and Clinical Opportunity

Myelodysplastic syndromes are enriched for somatic mutations in the pre-mRNA splicing apparatus, with recurrent acquired mutations most commonly occurring in SF3B1, SRSF2, U2AF1, and ZRSR2. These mutations appear to be early events in the pathogenesis of disease, and, given their frequency and central role in leukemogenesis, are of interest as potential therapeutic targets. Clinical trials are exploring targets that directly affect the spliceosome (splicing modulators or protein arginine methyltransferase 5 inhibitors) or that exploit possible vulnerabilities created by alternative splicing (inhibiting ATR). Future research is needed to explore novel targets and therapeutic combinations and understand how these mutations lead to clonal dominance.