SF3B1 encodes a core component of the U2 small nuclear ribonucleoprotein, involved in the recognition of the branchpoint sequence during RNA splicing. SF3B1 is one of several genes involved in RNA splicing that has been identified as recurrently mutated in MDS and other malignancies. SF3B1 is the most commonly mutated gene found in MDS (20-33% of MDS overall). SF3B1 mutations are highly associated with subtypes of MDS characterized by ring sideroblasts (MDS with ring sideroblasts and MDS with multilineage dysplasia and ring sideroblasts), present in ~80% of these patients. In addition, many cases (60-80%) of myelodysplastic/myeloproliferative neoplasm with ring sideroblast and thrombocytosis (MDS/MPN-RS-T) harbor SF3B1 mutations. SF3B1 mutations are also found in 12% of blastic plasmacytoid dendritic cell neoplasm, 4-7% of primary myelofibrosis, 5% of CMML, less than 5% of de novo AML and less than 5% of essential thrombocythemia and polycythemia vera. SF3B1 mutations tend to occur in exons 13-16 and appear to be enriched at codons Lys700, Lys666, His662, Arg625 and Glu622. Missense mutations have been reported in approximately 5-10% of cases of chronic lymphocytic leukemia (CLL) and are reported to be associated with del11q , unmutated IGHV and may predict an adverse prognosis in CLL. Mutations in splicing factor components are usually mutually exclusive. Among cases of CLL, SF3B1 mutations tend to be exclusive of NOTCH1 mutations according to one study. The presence of SF3B1 mutation has been included in the diagnostic criteria for MDS/MPN-RS-T and MDS-RS diagnosis in the 2016 revision of the WHO classification. SF3B1 mutations are independently associated with a more favorable prognosis in MDS (NCCN Guidelines for Myelodysplastic Syndromes) and are highly predictive for the presence of ring sideroblasts. SF3B1 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of therapy-related AML or elderly patients with de novo acute myeloid leukemia with worse clinical outcomes. SF3B1 mutations are associated with an unfavorable prognosis in essential thrombocythemia. SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known MDS-RS pathophysiology, suggesting a causal link.
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