Loss of cell-cycle control in RT from CLL cells. (A) Cell-cycle control by TP53, CDKN1A, CDKN2A, and CDKN2B blocks proliferation in CLL stage B cells after BCR stimulation. (B) Loss of TP53 and CDKN2A/B in RT allows transformed cells to proliferate past inactivated cell-cycle checkpoints. (C) Combined BCR- and CDK4/6-inhibition provides effective therapeutic response in preclinical RT mouse models. BCR-stim., BCR stimulation.