Spliceosomal mutation drives melanoma tumorigenesis via lineage-specific RAS activation.

Abstract

Mutations in splicing factors are recurrent across human cancers and drive widespread RNA splicing dysregulation. Among these, <i>SF3B1</i> is the most frequently mutated, yet its hotspot mutations exhibit lineage specificity, with <i>SF3B1</i>^R625 mutations predominantly found in melanoma and <i>SF3B1</i>^K700E in hematologic malignancies. However, the mechanistic basis for this cancer-type specificity remains unclear. Here, we demonstrate that <i>SF3B1</i>^R625H induces greater activation of alternative 3' splice site than <i>SF3B1</i>^K700E. Mechanistically, the polyadenine-enriched sequence surrounding cryptic branch point sites confers <i>SF3B1</i>^R625H selective advantage in aberrant splicing. This splicing bias leads to preferential missplicing of <i>NF1</i>, a RAS inhibitor, resulting in RAS hyperactivation and accelerated melanoma progression in mouse models. This study redefines the oncogenic paradigm of <i>SF3B1</i> mutations by demonstrating that distinct hotspot mutations exploit lineage-specific splicing vulnerabilities to drive tumorigenesis and establishes RAS activation as key mechanism underlying <i>SF3B1</i>^R625H-driven melanoma, positioning RAS pathway as tractable therapeutic target in <i>SF3B1</i>-mutant melanoma.