Human AML Stem Cells Remain Quiescent and Exhibit Chemotherapy Resistance within the Bone Marrow Endosteal Region.

AML is characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem cells (LSCs). We developed a primary human AML xenotransplantation model using newborn NOD/SCID/IL2rg−/ − mice. From 9 patients, 4x10 6 T cell-depleted BMMNCs were injected iv into sublethally irradiated recipients. At 3 months, newborn NOD/SCID/IL2rg−/ − recipients demonstrated superior engraftment efficiency compared with adult NOD/SCID/IL2rg−/ − and newborn NOD/SCID/b2m−/ − recipients (37.8%, 11.9%, 12.9%, respectively; p 3 cells engrafted dose-dependently. Transplanted hCD34+hCD38− cells gave rise to hCD34+hCD38−, hCD34+hCD38+ and hCD34− cells. In serial transplantation, injection of 10 3 purified hCD34+hCD38− cells resulted in long-term engraftment, giving rise to hCD34+hCD38− LSCs and hCD34+hCD38+/hCD34− blasts, demonstrating self-renewal and differentiation capacities of primary LSCs in vivo. We next examined homing and localization of LSCs using this model. In recipient femoral sections, 94.0% and 78.4% of hCD34+ cells were found in the endosteal region at day 3 and at 4 months after iv injection, respectively (10,065 cells and 24,973 cells examined, respectively; p