Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML

Abstract

In acute myeloid leukemia, a sub-population of quiescent cancer cells, called leukemia stem cells, is thought to be responsible for chemotherapy resistance and eventual recurrence of the disease. Saito et al. show that treatment with granulocyte colony-stimulating factor can overcome resistance to standard therapy by inducing cell cycle entry of the leukemia stem cells. Cancer stem cells have been proposed to be important for initiation, maintenance and recurrence of various malignancies, including acute myeloid leukemia (AML)1,2,3. We have previously reported4 that CD34+CD38− human primary AML stem cells residing in the endosteal region of the bone marrow are relatively chemotherapy resistant. Using a NOD/SCID/IL2rγnull mouse model of human AML, we now show that the AML stem cells in the endosteal region are cell cycle quiescent and that these stem cells can be induced to enter the cell cycle by treatment with granulocyte colony-stimulating factor (G-CSF). In combination with cell cycle-dependent chemotherapy, G-CSF treatment significantly enhances induction of apoptosis and elimination of human primary AML stem cells in vivo. The combination therapy leads to significantly increased survival of secondary recipients after transplantation of leukemia cells compared with chemotherapy alone.