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

Carrillo-Tornel, SalvadorChen-Liang, Tzu HuaZurdo, MaríaPuiggros Metje, Anna MariaGómez-Llonín, AndreaGarcía-Malo, María DoloresCuenca-Zamora, Ernesto JoséOrtuño, Francisco JoséHurtado López, Ana MaríaEspinet Solà, BlancaJerez, Andrés2023-02-282023-02-282022Carrillo-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.186090007-1048http://hdl.handle.net/10230/55947[AHEAD] Data de publicació electrónica: 27-12-2022Studies 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.application/pdfengThis 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.NOTCH1 mutation in chronic lymphocytic leukaemia is associated with an enhanced cell cycle G1/S transition and specific cyclin overexpression. Preclinical ground for targeted inhibitioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1111/bjh.18609NOTCH1Cell cycleChronic lymphocytic leukaemiaGene-expressionNext-generation sequencinginfo:eu-repo/semantics/openAccess