The BAF chromatin remodeling complex is a novel target of spliceosome dysregulation in SF3B1-mutated chronic lymphocytic leukemia

SF3B1 mutations are recurrent genetic aberrations in chronic lymphocytic leukemia (CLL) that are particularly enriched in the clinically aggressive stereotyped subset #2. To elucidate the effect of SF3B1 mutations on splicing, we performed RNA-sequencing on 100 CLL subset cases, including 35 subset #2 cases. Zooming in on subset #2, we identified 61 differentially expressed splicing events when comparing 17 SF3B1mut to 18 SF3B1wt cases. A key event concerned the inclusion of an alternative exon in BRD9, a BAF chromatin remodeling complex component. We also detected alternative splicing in 5 additional transcripts related to the BAF complex: ZEB1, PLSCR1, PAPD5, DCAF16, and DLST. Long-read RNA-sequencing confirmed these alternative splice transcripts. In conclusion, spliceosome dysregulation caused by mutated SF3B1 leads to multiple splicing events and altered BAF complex function, highlighting a potential novel therapeutic vulnerability in SF3B1mut CLL.EGA study EGAS00001006771