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

Author:

Hägerstrand DanielORCID,Oder BlažORCID,Cortese Diego,Qu Ying,Binzer-Panchal AmreiORCID,Österholm Cecilia,Del Peso Santos Teresa,Rabbani Leily,Asl Hassan Foroughi,Skaftason Aron,Ljungström Viktor,Lundholm August,Koutroumani Maria,Haider Zahra,Jylhä Cecilia,Mollstedt John,Mansouri Larry,Plevova Karla,Agathangelidis AndreasORCID,Scarfò LydiaORCID,Armand MarineORCID,Muggen Alice F.,Kay Neil E.ORCID,Shanafelt Tait,Rossi Davide,Orre Lukas M.ORCID,Pospisilova SarkaORCID,Barylyuk KonstantinORCID,Davi Frederic,Vesterlund MattiasORCID,Langerak Anton W.ORCID,Lehtiö JanneORCID,Ghia PaoloORCID,Stamatopoulos KostasORCID,Sutton Lesley-Ann,Rosenquist RichardORCID

Abstract

AbstractSF3B1 mutations are recurrent in chronic lymphocytic leukemia (CLL), particularly enriched in clinically aggressive stereotyped subset #2. To investigate their impact, we conducted RNA-sequencing of 18 SF3B1MUT and 17 SF3B1WT subset #2 cases and identified 80 significant alternative splicing events (ASEs). Notable ASEs concerned exon inclusion in the non-canonical BAF (ncBAF) chromatin remodeling complex subunit, BRD9, and splice variants in eight additional ncBAF complex interactors. Long-read RNA-sequencing confirmed the presence of splice variants, and extended analysis of 139 CLL cases corroborated their association with SF3B1 mutations. Overexpression of SF3B1K700E induced exon inclusion in BRD9, resulting in a novel splice isoform with an alternative C-terminus. Protein interactome analysis of the BRD9 splice isoform revealed augmented ncBAF complex interaction, while exhibiting decreased binding of auxiliary proteins, including SPEN, BRCA2, and CHD9. Additionally, integrative multi-omics analysis identified a ncBAF complex-bound gene quartet on chromosome 1 with higher expression levels and more accessible chromatin in SF3B1MUT CLL. Finally, Cancer Dependency Map analysis and BRD9 inhibition displayed BRD9 dependency and sensitivity in cell lines and primary CLL cells. In conclusion, spliceosome dysregulation caused by SF3B1 mutations leads to multiple ASEs and an altered ncBAF complex interactome, highlighting a novel pathobiological mechanism in SF3B1MUT CLL.

Publisher

Springer Science and Business Media LLC

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