SF3B1 gene

The SF3B1 gene is located on chromosome 2q33.1 and encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds the pre-mRNA upstream of the branch point of the intron in a sequence-independent manner and can anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the smaller U12-type spliceosome. The carboxy-terminal two-thirds of subunit 1 consists of 22 nonidentical tandem HEAT repeats that form rod-like helical structures. Alternative splicing gives rise to multiple transcript variants encoding different isoforms.

SF3B1 mutations have been described in several myeloid malignancies, most notably myelodysplastic syndromes (MDS), as well as in other hematologic malignancies, breast cancer, and uveal melanoma (UM). SF3B1 is one of several genes involved in RNA splicing that are consistently mutated in MDS and other malignancies. Mutations affecting SF3B1 are usually heterozygous point mutations suspected to be functionally pathogenic, with R625 and K700E described as important mutation hotspots. MDS patients with SF3B1 mutations have been reported to have better overall and event-free survival than their wild-type counterparts. Moreover, these mutations are highly associated with subtypes of MDS characterized by ring sideroblasts (refractory anemia with ring sideroblasts and refractory cytopenia with multilayer dysplasia and ring sideroblasts). In UM patients, SF3B1 mutations have been associated with chromosome 3 disomy, defining a subgroup at low risk of metastasis.

1. Malcovati L et al. (2020) SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS. Blood 136:157-170.