We therefore assessed the anti-tumor effects of dual MDM2/Bcl-2 inhibition with the small-molecule inhibitors idasanutlin and venetoclax in p53 wild-type AML models and explored the mechanism of action contributing to their synergistic activity in vitro through cell-cycle analysis, RNA sequencing (RNAseq), and time-course protein expression analysis. Here, MDM2 is linked to acute myeloid leukemia.