López-Oreja, IreneGohr, AndréPlaya-Albinyana, HeribertGiró, AriadnaArenas, FabiánHigashi, MorihiroTripathi, RupalLópez-Guerra, MónicaIrimia Martínez, ManuelAymerich, MartaValcárcel, J. (Juan)Bonnal, SophieColomer Pujol, Dolors2023-10-312023-10-312023López-Oreja I, Gohr A, Playa-Albinyana H, Giró A, Arenas F, Higashi M, Tripathi R, López-Guerra M, Irimia M, Aymerich M, Valcárcel J, Bonnal S, Colomer D. SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia. Life Sci Alliance. 2023 Aug 10;6(11):e202301955. DOI: 10.26508/lsa.2023019552575-1077http://hdl.handle.net/10230/58192Splicing 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 3' 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.application/pdfeng© 2023 López-Oreja et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.26508/lsa.202301955CancerMedical ResearchMolecular Biologyinfo:eu-repo/semantics/openAccess