The genetic inactivation of PSMB10 resulted in increased senescence and cytotoxic T lymphocyte (CTL) killing, as well as increased intracellular drug concentrations and drug-induced cellular senescence in different types of human AML cells, which also impeded human and murine leukemia initiation and stemness maintenance in vivo with a 19-fold decrease in the frequency of human LSCs and a 7.6-fold decrease of drug-resistant mouse LSCs, while normal hematopoietic cells remained unaffected. This evidence concerns the gene PSMB10 and acute myeloid leukemia.