Spliceosomal mutation drives melanoma tumorigenesis via lineage-specific RAS activation

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Mutations in splicing factors, particularly SF3B1, are common in human cancers and cause widespread RNA splicing dysregulation.
• SF3B1 hotspot mutations show cancer lineage specificity, with R625 mutations in melanoma and K700E in hematologic malignancies, but the underlying mechanisms are unknown.

Purpose of the Study:

• To elucidate the mechanistic basis for the cancer-type specificity of SF3B1 hotspot mutations.
• To investigate how SF3B1 mutations contribute to melanoma progression.

Main Methods:

• Comparative analysis of SF3B1 R625H and K700E mutations' effects on alternative 3' splice site activation.
• Investigation of the role of polyadenine-enriched sequences in aberrant splicing.
• Assessment of NF1 missplicing and RAS pathway activation in mouse models of SF3B1-mutant melanoma.

Main Results:

• SF3B1 R625H activates alternative 3' splice sites more significantly than SF3B1 K700E.
• Polyadenine-rich sequences near cryptic branch points facilitate SF3B1 R625H-mediated aberrant splicing.
• SF3B1 R625H mutations lead to preferential missplicing of NF1, causing RAS hyperactivation and accelerating melanoma progression in mouse models.

Conclusions:

• Distinct SF3B1 hotspot mutations leverage lineage-specific splicing vulnerabilities to drive tumorigenesis.
• RAS pathway activation is a key mechanism in SF3B1 R625H-driven melanoma.
• The RAS pathway represents a potential therapeutic target for SF3B1-mutant melanoma.