Leukemia　stem　cells　(LSCs)　have　critical　functions　in　acute　leukemia　(AL)　pathogenesis,　participating　in　its　initiation　and　relapse.　Thus,　identifying　new　molecules　to　eradicate　LSCs　represents　a　high　priority　for　AL　management.　This　work　identified　E35,　a　novel　Emodin　derivative,　which　strongly　inhibited　growth　and　enhanced　apoptosis　of　AL　stem　cell　lines,　and　primary　stem　and　progenitor　cells　from　AL　cases,　while　sparing　normal　hematopoietic　cells.　Furthermore,　functional　assays　in　cultured　cells　and　animals　suggested　that　E35　preferentially　ablated　primitive　leukemia　cell　populations　without　impairing　their　normal　counterparts.　Moreover,　molecular　studies　showed　that　E35　remarkably　downregulated　drug-resistant　gene　and　dramatically　inhibited　the　Akt/mammalian　target　of　rapamycin　signaling　pathway.　Notably,　the　in　vivo　anti-LSC　activity　of　E35　was　further　confirmed　in　murine　xenotransplantation　models.　Collectively,　these　findings　indicate　E35　constitutes　a　novel　therapeutic　candidate　for　AL,　potentially　targeting　leukemia　stem　and　progenitor　cells.　©　2020　The　Authors.　Journal　of　Cellular　Physiology　published　by　Wiley　Periodicals,　Inc.