Cyclin C (CCNC) has been shown to promote cell cycle progression and transcription, but little is known about its functions in vivo. Li et al. used conditional Ccnc knockout mice to show that CCNC and cyclin-dependent kinase (CDK) complexes phosphorylate the NOTCH1 intracellular domain (NICD) to promote its degradation; therefore, mice lacking CCNC have higher NICD levels. Ccnc knockout or heterozygosity promoted development of T cell acute lymphoblastic leukaemia (T-ALL) in collaboration with T-ALL oncogene expression in mice. In human T-ALL samples, heterozygous deletions of CCNC were frequently observed, as were point mutations that prevented NICD phosphorylation by CCNC–CDK.