NOTCH1 mutation in chronic lymphocytic leukaemia is associated with an enhanced cell cycle G1/S transition and specific cyclin overexpression. Preclinical ground for targeted inhibition

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• dc.contributor.author Carrillo-Tornel, Salvador
• dc.contributor.author Chen-Liang, Tzu Hua
• dc.contributor.author Zurdo, María
• dc.contributor.author Puiggros Metje, Anna Maria
• dc.contributor.author Gómez-Llonín, Andrea
• dc.contributor.author García-Malo, María Dolores
• dc.contributor.author Cuenca-Zamora, Ernesto José
• dc.contributor.author Ortuño, Francisco José
• dc.contributor.author Hurtado López, Ana María
• dc.contributor.author Espinet Solà, Blanca
• dc.contributor.author Jerez, Andrés
• dc.date.accessioned 2023-02-28T07:36:47Z
• dc.date.available 2023-02-28T07:36:47Z
• dc.date.issued 2022
• dc.description [AHEAD] Data de publicació electrónica: 27-12-2022
• dc.description.abstract Studies prior to next-generation sequencing (NGS) showed that the frequent indolent course of chronic lymphocytic leukaemia (CLL) is related to most cells remaining quiescent in the G0 -G1 cell cycle phase, due to the expression of dysregulated cyclin genes. Of note, the activating nature of the NOTCH1 mutation in T lymphoblastic leukaemia also drives the dysregulation of cell cycle genes. Our goal was to comprehensively revisit the cell cycle in NOTCH1-mutated CLL (NOTCH1MUT ) to test for potential therapeutic targets. Among 378 NGS-annotated CLL cases, NOTCH1MUT cells displayed a unique transcriptome profile of G0 -G1 cell cycle components, with an overexpression of early-phase effectors, reaching a 38-, 27- and ninefold change increase for the complex elements CCND3, CDK4 and CDK6, respectively. This NOTCH1MUT cells' profile was related to more cells traversing through the cell cycle. In-vitro targeted inhibition of NOTCH1 gamma-secretase and CDK4/6 reversed the distribution of cells through the cycle phases and enhanced the killing of NOTCH1MUT CLL cells, suggesting new therapeutic approaches.
• dc.format.mimetype application/pdf
• dc.identifier.citation Carrillo-Tornel S, Chen-Liang TH, Zurdo M, Puiggros A, Gómez-Llonín A, García-Malo MD, et al. NOTCH1 mutation in chronic lymphocytic leukaemia is associated with an enhanced cell cycle G1/S transition and specific cyclin overexpression. Preclinical ground for targeted inhibition. Br J Haematol. 2022 Dec 27. DOI: 10.1111/bjh.18609
• dc.identifier.doi http://dx.doi.org/10.1111/bjh.18609
• dc.identifier.issn 0007-1048
• dc.identifier.uri http://hdl.handle.net/10230/55947
• dc.language.iso eng
• dc.publisher Wiley
• dc.rights This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword NOTCH1
• dc.subject.keyword Cell cycle
• dc.subject.keyword Chronic lymphocytic leukaemia
• dc.subject.keyword Gene-expression
• dc.subject.keyword Next-generation sequencing
• dc.title NOTCH1 mutation in chronic lymphocytic leukaemia is associated with an enhanced cell cycle G1/S transition and specific cyclin overexpression. Preclinical ground for targeted inhibition
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion