SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia

Splicing factor 3B subunit 1 (SF3B1) is involved in pre-mRNA branch site recognition and is the target of antitumor-splicing inhibitors. Mutations in SF3B1 are observed in 15% of patients with chronic lymphocytic leukemia (CLL) and are associated with poor prognosis, but their pathogenic mechanisms remain poorly understood. Using deep RNA-sequencing data from 298 CLL tumor samples and isogenic SF3B1 WT and K700E-mutated CLL cell lines, we characterize targets and pre-mRNA sequence features associated with the selection of cryptic 39 splice sites upon SF3B1 mutation, including an event in the MAP3K7 gene relevant for activation of NF-KB signaling. Using the H3B-8800 splicing modulator, we show, for the first time in CLL, cytotoxic effects in vitro in primary CLL samples and in SF3B1-mutated isogenic CLL cell lines, accompanied by major splicing changes and delayed leukemic infiltration in a CLL xenotransplant mouse model. H3B-8800 displayed preferential lethality towards SF3B1- mutated cells and synergism with the BCL2 inhibitor venetoclax, supporting the potential use of SF3B1 inhibitors as a novel therapeutic strategy in CLL.

Automated summary

In this study, the researchers used deep RNA sequencing data to analyze CLL tumor samples and SF3B1 wild-type and K700E-mutated CLL cell lines. They identified protein pre-mRNA features and cryptic 39 splice site events associated with SF3B1 mutation. They also demonstrated the cytotoxic effects of the splicing modulator H3B-8800 in CLL samples and SF3B1-mutated cell lines, and its potential therapeutic use in combination with the BCL2 inhibitor venetoclax in CLL.