The findings from a study to pinpoint how splicing factor 3b subunit 1 (SF3B1) mutations affect cases of chronic lymphocytic leukemia (CLL) were published in Leukemia.
“Spliceosome dysregulation caused by SF3B1 mutations leads to multiple alternative splicing events (ASEs) and an altered non-canonical BAF (ncBAF) complex interactome, highlighting a novel pathobiological mechanism in SF3B1[-mutated] CLL,” wrote investigator Daniel Hägerstrand, PhD, of the Karolinska Institutet in Stockholm, Sweden.
The study investigators conducted RNA-sequencing of CLL stereotyped subset #2 cases, where 18 cases had SF3B1 mutation and 17 did not. They identified 80 significant ASEs in these cases, and the presence of splice variants was confirmed on long-read RNA-sequencing. Results from a subsequent analysis performed on 139 CLL cases supported that an association exists between SF3B1 mutations and these splice variants.
“These ASEs impact the ncBAF complex function from multiple vantage points with expected chromatin modulatory effects and subsequently altered gene expression,” Dr. Hägerstrand remarked.
Through protein interactome analysis of a bromodomain-containing 9 (BRD9) novel splice isoform that they identified, the investigators determined that overexpression of SF3B1K700E led to augmented ncBAF complex interaction and reduced binding of auxiliary proteins.
In an integrative multi-omics analysis, the investigators also found that in SF3B1-mutated CLL, chromosome 1 features a ncBAF complex-bound gene quartet with increased expression levels and more accessible chromatin.
“Our findings suggest functional consequences of SF3B1 mutations and highlight ncBAF complex subunits as potential targets for therapeutic exploration in CLL,” Dr. Hägerstrand wrote.
The investigators also identified BRD9 dependency and sensitivity in primary CLL cells and cell lines on BRD9 inhibition and the Cancer Dependency Map analysis they performed.
Reference
Hägerstrand D, Oder B, Cortese D, et al. The non-canonical BAF chromatin remodeling complex is a novel target of spliceosome dysregulation in SF3B1-mutated chronic lymphocytic leukemia. Leukemia. 2024. doi:10.1038/s41375-024-02379-4