López Oreja, IreneGohr, AndrePlaya-Albinyana, HeribertGiró, AriadnaArenas Ríos, FabiánHigashi, MorihiroTripathi, RupalLópez Guerra, MónicaIrimia Martínez, ManuelAymerich Gregorio, MartaValcárcel Juárez, JuanBonnal, SophieColomer Pujol, Dolors2025-11-122025-11-122023-08-102575-1077https://hdl.handle.net/2445/224326Splicing 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.26 p.application/pdfengcc-by (c) López Oreja, Irene et al., 2023http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/article7541672025-11-12info:eu-repo/semantics/openAccess37562845