Chemotherapy is the primary treatment option for acute myeloid leukemia (AML), but leukemic stem cells (LSCs) can survive chemotherapy for disease recurrence and refractory. Here, we found that AML cells obtained from relapsed patients had increased autophagy levels than de novo AML cells. Furthermore, Doxorubicin (DOX) treatment stimulated autophagy in LSCs by repressing the mTOR pathway, and pharmaceutical inhibition of autophagy rendered chemoresistant LSCs sensitive to DOX treatment in

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... F9 induced murine AML. Moreover, we developed a self-assembled leucine polymer, which activated mTOR to inhibit autophagy in AML cells by releasing leucine. The leucine polymer loaded DOX (Leu-DOX) induced much less autophagy but more robust apoptosis in AML cells than the DOX treatment. Notably, the leucine polymer and Leu-DOX were specifically uptaken by AML cells and LSCs but not by normal hematopoietic cells and hematopoietic stem/progenitor cells in the bone marrow. Consequently, Leu-DOX efficiently reduced LSCs and prolonged the survival of AML mice, with limited myeloablation and tissue damage side effects than DOX treatment. Overall, we proposed that the newly developed Leu-DOX is an effective autophagy inhibitor and an ideal drug to efficiently eliminate LSCs, thus serving as a revolutionary strategy to enhance the chemotherapy efficacy in AML.