The commonly accepted paradigm that HSCs are the target cells of RI-AML was recently challenged by Hirouchi et al. Instead, they concluded that AML stem cells can arise from long-lived HSCs, short-lived multipotent progenitors (MPPs), and even common myeloid progenitors (CMPs) that have acquired self-renewal potential, with the inactivation of Dusp2 on Chr2 being a likely contributor. Here, DUSP2 is linked to acute myeloid leukemia.