Our results not only revealed that PIK3IP1 downregulation may be the key reason responsible for the PI3K/AKT re-activation-mediated resistance of the BCL-2 inhibitor in cancer cells, but also highlighted the effect of targeting the EZH2/PIK3IP1 axis to suppress the PI3K/AKT/mTOR signaling anti-effect in AML. Here, AKT1 is linked to acute myeloid leukemia.