The SF3b complex in cancer: structural basis, molecular mechanisms, and therapeutic opportunities.

Abstract

Aberrant alternative splicing is increasingly recognized as a fundamental driver of cancer initiation and progression. The splicing factor 3b (SF3b) complex, an essential component of the U2 small nuclear ribonucleoprotein (snRNP), plays a pivotal role in branch point sequence (BPS) recognition and in coordinating spliceosome assembly and activation. Recent advances in cryo-electron microscopy (cryo-EM) have revealed the structural plasticity of the SF3b complex, highlighting its dynamic transition between open and closed conformations that stabilize pre-mRNA substrates during the splicing cycle. Genetic and functional perturbations of SF3b, particularly recurrent mutations in its core subunit SF3B1, are frequently observed in human malignancies, most prominently in myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). These alterations reshape splice site selection, generate aberrant transcript isoforms, and reprogram cancer-relevant signaling pathways. In this review, we integrate current knowledge of the molecular architecture and regulatory dynamics of the SF3b complex with its emerging roles in cancer-associated splicing programs. We discuss the consequences of SF3b mutations and non-mutational dysregulation on transcriptome remodeling, genome stability, and tumor cell fitness, as well as the contribution of post-translational modifications of SF3b components to splicing control. Furthermore, we critically evaluate recent progress in targeting the SF3b complex, focusing on the structural basis of SF3b inhibitors, insights gained from preclinical studies, and lessons learned from early-phase clinical trials. Collectively, this review positions the SF3b complex as a disease-modifying hub at the intersection of RNA splicing and cancer biology, and highlights the opportunities and challenges associated with therapeutically targeting spliceosome components in oncology.