SF3B1, SRSF2, and U2AF function in splicing. (A) The U1 small nuclear ribonucleoprotein (snRNP) and U2AF initially bind to the 5′′ and 3′′ splice sites, respectively. This is followed by binding of the SF3B-containing U2 snRNP and, subsequently, assembly of a multiprotein complex (including U4, U5, and U6 snRNPs) known as the “spliceosome,” which then leads to excision of the intervening intron. Further sequences within exons and introns act as splicing enhancer or silencer elements and are bound by proteins, such as hnRNPs and SR proteins (eg, SRSF2). These RBPs allow splicing to be controlled in a tissue-developmental stage– and stimulus-specific manner. (B) SRSF2 binds equally to GGNG and CCNG exonic splicing enhancers (ESE) to allow expression of EZH2 in healthy HSPCs. In MDS/chronic myelomonocytic leukemia, the P95H mutation of SRSF2 has preferential binding to the CCNG ESE, giving rise to a splice variant of EZH2 including an exon with a premature stop codon that is degraded by NMD.