MCL clones with gene knockout or transgenic (over)expression of CDKN2A, MYC, CDK4, and RB1 were used to estimate impact of these aberrations on sensitivity to palbociclib, and venetoclax.<h4>Results</h4>Co-targeting MCL cells with palbociclib and venetoclax induced cytotoxic synergy in vitro and in vivo. This evidence concerns the gene RB1 and mantle cell lymphoma.