Fig. 6

a Role of abnormality of RNA splicing in the pathogenesis of SF3B1-mutated MDS. In hematopoietic cells, normal spliceosomes implement roughly half of the splicing events, while the other half is performed by spliceosomes containing a mutant SF3B1 splicing factor, which alters the recognition of RNA branch points and renders the preferred usage of cryptic 3′ splice sites located 10–30 base pairs farther upstream of canonical sites, finally causing aberrant transcripts of several genes or in-frame isoforms production. However, just small quantities of abnormal transcripts are detectable in SF3B1-mutated myelodysplastic cells owing to the bulk of abnormal transcripts’ rapid degradation through nonsense-mediated decay, which is primarily caused by the inserted nucleotide sequence containing a premature termination codon. b Synergistic interaction of aberrant splicing and epigenetic dysregulation in MDS. Mutation of SRSF2 renders the preference alteration of the neomorphic splicing factor to specific exonic splicing enhancer motifs, in turn causing alternative exon usage. Aberrant transcripts with a premature stop codon will be generated in the process, with rapid degradation through nonsense-mediated decay or the production of mutated proteins, resulting in different pathological outcomes. Mutation of IDH2 (R140Q) gives rise to the activation of the neomorphic enzyme and, in turn, DNA hypermethylation, which sabotages epigenetic regulators’ function and drives the malignant advancement of the disease