Spliceosomal disruption of the non-canonical BAF complex in cancer

Daichi Inoue, Guo Liang Chew, Bo Liu, Brittany C. Michel, Joseph Pangallo, Andrew R. D’Avino, Tyler Hitchman, Khrystyna North, Stanley Chun Wei Lee, Lillian Bitner, Ariele Block, Amanda R. Moore, Akihide Yoshimi, Luisa Escobar-Hoyos, Hana Cho, Alex Penson, Sydney X. Lu, Justin Taylor, Yu Chen, Cigall KadochOmar Abdel-Wahab, Robert K. Bradley

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L5–7. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.

Original languageEnglish (US)
Pages (from-to)432-436
Number of pages5
Issue number7778
StatePublished - Oct 17 2019
Externally publishedYes

ASJC Scopus subject areas

  • General


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