Spliceosomal disruption of the non-canonical BAF complex in cancer.

Abstract

SF3B1 is the most commonly mutated RNA splicing factor in cancer1–4, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here, we integrated pan-cancer splicing analyses with a positive enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, a core component of the recently described GLTSCR1/1L-containing non-canonical BAF (ncBAF) chromatin remodeling complex5–7. Mutant SF3B1 recognizes an aberrant deep intronic branchpoint within BRD9, thereby inducing inclusion of an endogenous retroviral element-derived poison exon and BRD9 mRNA degradation. BRD9 depletion causes loss of ncBAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumor suppressor in uveal melanoma (UVM), such that correcting BRD9 mis-splicing in SF3B1-mutant cells with antisense oligonucleotides (ASOs) or CRISPR-directed mutagenesis suppresses tumor growth. Our results implicate ncBAF disruption in the diverse cancers carrying SF3B1 mutations and suggest a mechanism-based therapeutic for these malignancies.