The FDA-approved CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib exert anti-proliferative and pro-apoptotic effects in most MCL cell lines and primary neoplastic MCs and CD34+/CD38− LSC isolated from patients with AdvSM and synergize with KIT-targeting TKIs in producing growth arrest. Here, CDK6 is linked to mantle cell lymphoma.