We here demonstrate that the combined inhibition of BCL-2 and MCL-1 circumvents the resistance in TP53-deleted or mutant-AML to individual BH3 mimetics and synergistically induces TP53-independent profound apoptosis in AML cells and AML stem/progenitor cells in vitro and in vivo. The gene discussed is MCL1; the disease is acute myeloid leukemia.