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Hematopoietic stem cells supplying all mature hematopoietic and immune cells throughout life provide protection from various diseases. However, in some hematopoietic malignancies, hematopoietic stem/progenitor cells are hit by genetic and/or epigenetic oncogenic events and transform into leukemic stem cells. As is proposed in solid cancer, leukemia stem cells (LSCs) may be important in initiation, resistance to therapy, and post-remission relapse in patients with acute myeloid leukemia (AML). We aimed to clarify the role of LSCs in AML relapse and to develop therapeutic strategies targeting human LSCs.To do so, we established a mouse model recapitulating human AML by transplantation of purified human leukemic cells into NOD/SCID/IL2rgKO newborns. Using this xenogeneic transplantation system, we demonstrated that CD34 + CD38− AML cells satisfy the criteria for LSCs: in vivo leukemia initiation, propagation of non-stem leukemic cells, and self-renewal capacity. Chemotherapy treatment of AML-engrafted recipients demonstrated that LSCs within the endosteal region are resistant to chemotherapy. Cell cycle analysis by flow cytometry and immuno-fluorescence studies further revealed that AML LSCs at the niche are cell cycle quiescent and non-stem AML cells are actively cycling. These findings suggest that cell cycle quiescence of LSCs within the endosteal niche may, at least partially, account for their chemo-resistance. To improve the clinical outcome in AML patients with unfavorable prognosis factors, elimination of chemotherapy-resistant AML stem cells through targeting LSC-specific molecules could be a novel therapeutic strategy.