Spliceosomal mutation drives melanoma tumorigenesis via lineage-specific RAS activation
- Ruixin Jiang
- Peiqi Xing
- Jindou Xie
- Gang Bai
- Yuzhu Zhang
- Pengcong Hou
- Hao Luo
- Yanni Ma
- Ruixin Liu
- Yang Zheng
- Xiangyu Chen
- Bin Jiang
- Jing Huang
- Yanjie Zhang
- A. Hunter Shain
- Ming Lei
- Robert L. Judson-Torres
- Jing Ye
- Zhaoqi Liu
- Hanlin Zeng
2026-05-01
Mutations in splicing factors are recurrent across human cancers and drive widespread RNA splicing dysregulation. Among these, SF3B1 is the most frequently mutated, yet its hotspot mutations exhibit lineage specificity, with SF3B1 R625 mutations predominantly found in melanoma and SF3B1 K700E in hematologic malignancies. However, the mechanistic basis for this cancer-type specificity remains unclear. Here, we demonstrate that SF3B1 R625H induces greater activation of alternative 3′ splice site than SF3B1 K700E . Mechanistically, the polyadenine-enriched sequence surrounding cryptic branch point sites confers SF3B1 R625H selective advantage in aberrant splicing. This splicing bias leads to preferential missplicing of NF1 , a RAS inhibitor, resulting in RAS hyperactivation and accelerated melanoma progression in mouse models. This study redefines the oncogenic paradigm of SF3B1 mutations by demonstrating that distinct hotspot mutations exploit lineage-specific splicing vulnerabilities to drive tumorigenesis and establishes RAS activation as key mechanism underlying SF3B1 R625H -driven melanoma, positioning RAS pathway as tractable therapeutic target in SF3B1 -mutant melanoma.