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The myelodysplastic syndromes (MDS) are common myeloid malignancies showing frequent progression to acute myeloid leukemia (AML). Pre-mRNA splicing is an essential cellular process carried out by the spliceosome. Mutations in splicing factor genes (including SF3B1, SRSF2, U2AF1 and ZRSR2) occur in over half of MDS patients and result in aberrant pre-mRNA splicing of many target genes, implicating aberrant spliceosome function in MDS disease pathogenesis. Recent functional studies have illuminated the impact on hematopoiesis of some aberrantly spliced target genes associated with splicing factor mutations. Emerging data show that the commonly mutated splicing factors have convergent effects on aberrant splicing of mRNAs that promote NF-κB signaling and on R-loop elevation leading to DNA damage, providing novel insights into MDS disease pathophysiology. It is recognized that the survival of splicing factor mutant cells is dependent on the presence of the wildtype allele, providing a rationale for the use of spliceosome inhibitors in splicing factor mutant MDS. Pre-clinical studies involving E7107 and H3B-8800 have shown the potential of these spliceosome inhibitors for the treatment of splicing factor mutant MDS and AML.

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Myelodysplastic syndromes, NF-κB signaling, R-loops, RNA splicing, Spliceosome inhibitors, Splicing factor gene mutations