Blanca Espinet

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 G 0 –G 1 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 ( NOTCH1 MUT ) to test for potential therapeutic targets. Among 378 NGS‐annotated CLL cases, NOTCH1 MUT cells displayed a unique transcriptome profile of G 0 –G 1 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 NOTCH1 MUT 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 NOTCH1 MUT CLL cells, suggesting new therapeutic approaches.