Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML.
Cancer stem cells have been proposed to be important for initiation, maintenance and recurrence of various malignancies, including acute myeloid leukemia (AML). We have previously reported 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/IL2rgamma(null) 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.
Saito
Yoriko
Y
Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
Uchida
Naoyuki
N
Tanaka
Satoshi
S
Suzuki
Nahoko
N
Tomizawa-Murasawa
Mariko
M
Sone
Akiko
A
Najima
Yuho
Y
Takagi
Shinsuke
S
Aoki
Yuki
Y
Wake
Atsushi
A
Taniguchi
Shuichi
S
Shultz
Leonard D
LD
Ishikawa
Fumihiko
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
D016179:Granulocyte Colony-Stimulating Factor