Pathway Mutations in the Splicing Machinery in Myeloid Neoplasms

Abstract SCI-14

During the past decade, significant progress has been made in our understanding of the molecular pathogenesis of myelodysplastic syndromes (MDS) and related myeloid neoplasms, in which one of the major findings was frequent mutations of genes in epigenetic regulation, such as DNA methylation (DNMT3A, TET2, and IDH1/2) and chromatin modifications (ASXL1, EZH2, EED, and SUZ12). They are also found in comparable or even higher fractions of other myeloid neoplasms, underscoring the common impact of deregulated epigenetic regulation on myeloid leukemogenesis. On the other hand, a new class of pathway mutations has been uncovered recently that commonly involve the RNA splicing machinery (1, 2, 3). Thus, at least eight different components of the machinery, invariably engaged in the 3' splice site recognition, have been reported to be mutated in as high as 45 percent to 85 percent of cases with different subtypes of MDS and related myeloid neoplasms mostly in a mutually exclusive manner. This indicates that the 3' splice site recognition is the functional target of these mutations. There exist discrete mutational hotspots in three out of four major targets, including SF3B1, SRSF2, U2AF35, and ZRSR2, and these mutant alleles can induce abnormal RNA splicing, indicating the gain-of-function nature of the mutations (2). Splicing factor mutations are largely specific to myelodysplasia phenotypes but relatively rare in acute myeloid leukemia and myeloproliferative neoplasms (2), suggesting their primary roles in the pathogenesis of myelodysplasia. The genotype-phenotype association is especially prominent in the case of SF3B1 mutations, which were found in 76 percent to 83 percent of cases of refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) (1, 2). In this session, the updated findings on the spliceosome mutations found in myelodysplasia, including their clinical and functional aspects, will be discussed.