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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/224326
SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia
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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-κB 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.
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LÓPEZ OREJA, Irene, et al. SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia. Life Science Alliance. 2023. Vol. 6, num. 11. ISSN 2575-1077. [consulted: 19 of August of 2026]. Available at: https://hdl.handle.net/2445/224326