Notably, the combination of ATRA with the CDK4/6 inhibitor (CDK4/6i) palbociclib induces enlarged PML-NB-dependent cytotoxicity through conflicting cell cycle signals, driven by ATRA-dependent activation of mitogenic ERK signaling under conditions of cell cycle arrest in non-APL leukemia. The gene discussed is CDK4; the disease is acute promyelocytic leukemia.