Here, we report that DS in combination with Cu has a potent and selective anti-leukemia property in vitro against leukemia stem-like cells (e.g., CD34+/CD38− KG1α and Kasumi-1 cells and primary CD34+ cells isolated from AML patients) as well as is highly effective in vivo in CD34+/CD38− leukemic cell-derived xenograft mouse models, in association with induction of apoptosis via activation of the stress-related ROS-JNK pathway and inhibition of the pro-survival Nrf2 and NF-κB pathways. This evidence concerns the gene MAPK8 and acute myeloid leukemia.