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

Summary 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.