Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region.
Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2r gamma(null) mice carrying a complete null mutation of the cytokine gamma c upon the SCID background. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle-dependent cytotoxic therapy. Global transcriptional profiling identified LS cell-specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.
Ishikawa
Fumihiko
F
Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama 230-0045, Japan. f_ishika@rcai.riken.jp
Yoshida
Shuro
S
Saito
Yoriko
Y
Hijikata
Atsushi
A
Kitamura
Hiroshi
H
Tanaka
Satoshi
S
Nakamura
Ryu
R
Tanaka
Toru
T
Tomiyama
Hiroko
H
Saito
Noriyuki
N
Fukata
Mitsuhiro
M
Miyamoto
Toshihiro
T
Lyons
Bonnie
B
Ohshima
Koichi
K
Uchida
Naoyuki
N
Taniguchi
Shuichi
S
Ohara
Osamu
O
Akashi
Koichi
K
Harada
Mine
M
Shultz
Leonard D
LD
D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow; D002455:Cell Division; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010006:Osteoblasts