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

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  • dc.contributor.author López-Oreja, Irene
  • dc.contributor.author Gohr, André
  • dc.contributor.author Playa-Albinyana, Heribert
  • dc.contributor.author Giró, Ariadna
  • dc.contributor.author Arenas, Fabián
  • dc.contributor.author Higashi, Morihiro
  • dc.contributor.author Tripathi, Rupal
  • dc.contributor.author López-Guerra, Mónica
  • dc.contributor.author Irimia Martínez, Manuel
  • dc.contributor.author Aymerich, Marta
  • dc.contributor.author Valcárcel, J. (Juan)
  • dc.contributor.author Bonnal, Sophie
  • dc.contributor.author Colomer Pujol, Dolors
  • dc.date.accessioned 2023-10-31T07:33:30Z
  • dc.date.available 2023-10-31T07:33:30Z
  • dc.date.issued 2023
  • dc.description.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.
  • dc.description.sponsorship The work of the authors is supported by the Spanish Ministry of Science and Innovation through the Plan Estatal de Investigación Científica y Técnica y de Innovación (RTI2018-094584-B-I00; PID2021-123165OB-I00; BFU-2017-89308-P, PID2020-114630GB-I00) and was cofounded by the European Regional Development Fund (ERDF), European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program ERC-AdG-LS2-670146 l, CERCA program from Generalitat de Catalunya, Centre of Excellence Severo Ochoa Award (CEX2020-001049) to the Centre for Genomic Regulation of the Barcelona Institute of Science and Technology, Centro de Investigación Biomédica en Cáncer (CIBERONC) (CB16/12/334), Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya (2017 SGR 1009; 2021 SGR-1294) and Asociación Española Contra el Cancer (AECC) (PRYGN223298VALC). We thank Elias Campo for sharing transcriptomics data from ICGC consortium and for reviewing the manuscript. We thank Suzanne Mays, Estefania Mancini, Malgorzata Rogalska, and Ferran Nadeu for their help and all the laboratory members from Juan Valcarcel’s group.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation 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
  • dc.identifier.doi http://dx.doi.org/10.26508/lsa.202301955
  • dc.identifier.issn 2575-1077
  • dc.identifier.uri http://hdl.handle.net/10230/58192
  • dc.language.iso eng
  • dc.publisher Life Science Alliance
  • dc.relation.ispartof Life Sci Alliance. 2023 Aug 10;6(11):e202301955
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/670146
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094584-B-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-123165OB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU-2017-89308-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114630GB-I00
  • dc.rights © 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/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cancer
  • dc.subject.keyword Medical Research
  • dc.subject.keyword Molecular Biology
  • dc.title SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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