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, Salvador; Chen-Liang, Tzu Hua; Zurdo, María; Puiggros Metje, Anna Maria; Gómez-Llonín, Andrea; García-Malo, María Dolores; Cuenca-Zamora, Ernesto José; Ortuño, Francisco José; Hurtado López, Ana María; Espinet Solà, Blanca; Jerez, Andrés

doi:http://dx.doi.org/10.1111/bjh.18609

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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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

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.