Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability

Area of Science:

• Molecular Biology
• Cancer Genomics
• RNA Splicing

Background:

• Oncogenic SF3B1 mutations are prevalent in myeloid cancers, CLL, and solid tumors.
• Previous research focused on SF3B1's role in missplicing mRNA coding sequences, leading to loss-of-function.
• The impact of SF3B1 mutations on non-coding mRNA regions remained largely unexplored.

Purpose of the Study:

• To systematically analyze the effects of mutant SF3B1 on non-coding mRNA regions across various cancer types.
• To investigate the mechanistic link between SF3B1 mutations and altered protein levels.
• To explore novel therapeutic strategies targeting SF3B1-driven oncogenesis.

Main Methods:

• Systematic analysis of mRNA splicing alterations in non-coding regions in cell lines and patient specimens with SF3B1 mutations.
• Detailed study of the DCAF16 gene, including its 5' and 3' untranslated regions (UTRs).
• Investigation of novel small molecules targeting the DCAF16-DDB1/CUL4 E3 ubiquitin ligase complex.

Main Results:

• Identified numerous novel and reproducible splicing alterations in non-coding mRNA regions due to SF3B1 mutations.
• Demonstrated that SF3B1 mutations increase DCAF16 protein levels via alterations in its 5' and 3' UTRs, a gain-of-function mechanism.
• Developed novel protein degrader molecules showing selective efficacy against SF3B1-mutant cancers and CLL specimens due to elevated DCAF16.

Conclusions:

• Oncogenic SF3B1 dysregulates transcript untranslated regions, leading to increased target protein levels.
• Elevated DCAF16 protein in SF3B1-mutant cells provides a therapeutic vulnerability.
• Targeting the DCAF16-DDB1/CUL4 complex represents a promising new therapeutic strategy for SF3B1-mutant neoplasms.