SF3B1

SF3B1 (splicing factor 3B subunit 1) is a gene that encodes a component of the U2 small nuclear ribonucleoprotein complex involved in pre-mRNA splicing. The SF3B1 protein is a large HEAT-repeat containing subunit that participates in the recognition of the branch point and the 3' splice site as part of the U2 snRNP within the spliceosome. In human cells, SF3B1 functions in concert with other SF3B components to stabilize the pre-mRNA–U2 snRNP interaction and regulate splice site selection.

Mutations in SF3B1 are recurrent somatic events across a range of cancers, most notably myelodysplastic syndromes with ring sideroblasts and chronic lymphocytic leukemia, as well as some solid tumors. Mutations cluster in the HEAT-repeat region of the protein and include known hotspots such as K700E; these missense changes alter 3' splice site choice, often producing aberrant splicing and cryptic transcripts rather than a simple loss of SF3B1 function.

Clinical significance varies by disease context. In myelodysplastic syndromes, SF3B1 mutations are strongly associated with the ring sideroblast phenotype and are generally linked to a more favorable prognosis compared with SF3B1-wild-type cases. In chronic lymphocytic leukemia and other malignancies, SF3B1 mutations have been associated with adverse outcomes and poorer response to some therapies, reflecting context-specific effects.

Therapeutically, the SF3B1-containing spliceosome represents a target for experimental cancer treatments. Spliceosome modulators and inhibitors aim to disrupt SF3B1 function or its interactions, showing selective activity in SF3B1-mutant cells in preclinical models and early clinical studies.