We show that the inhibition of DNA-PK with the selective inhibitor, M3814, potentiates the ATM/p53 response to DNA DSB induced by IR or topoisomerase II inhibitors (e.g., etoposide, daunorubicin, and idarubicin) in acute leukemia cells, leading to increased p53-dependent apoptosis. Here, PRKDC is linked to acute leukemia.