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

López-Oreja, Irene; Gohr, André; Playa-Albinyana, Heribert; Giró, Ariadna; Arenas, Fabián; Higashi, Morihiro; Tripathi, Rupal; López-Guerra, Mónica; Irimia Martínez, Manuel; Aymerich, Marta; Valcárcel, J. (Juan); Bonnal, Sophie; Colomer Pujol, Dolors

doi:http://dx.doi.org/10.26508/lsa.202301955

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

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López-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.202301955

Abstract

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 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.