Journal Article

Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region

Tanaka, Toru, Ishikawa, Fumihiko, Nakamura, Ryu, Harada, Mine, Kitamura, Hiroshi, Saito, Noriyuki, Hijikata, Atsushi, Saito, Yoriko, Ohara, Osamu, Taniguchi, Shuichi, Yoshida, Shuro, Miyamoto, Toshihiro, Shultz, Leonard D, Lyons, Bonnie, Ohshima, Koichi, Tomiyama, Hiroko, Tanaka, Satoshi, Fukata, Mitsuhiro, Akashi, Koichi, Uchida, Naoyuki

2007

Overview

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 1 , 2 , 3 . 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)2rγ null mice carrying a complete null mutation of the cytokine γc upon the SCID background 4 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Animals / Apoptosis / Bioinformatics / Biological and medical sciences / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Bone Marrow / Cell Division / Chemotherapy / Drug Resistance, Neoplasm / Fundamental and applied biological sciences. Psychology / Gene Expression Profiling / Health. Pharmaceutical industry / Humans / Industrial applications and implications. Economical aspects / letter / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - pathology / Life Sciences / Mice / Mice, Mutant Strains / Miscellaneous / Models, Biological / Mutation / Neoplasm Transplantation / Neoplastic Stem Cells - cytology / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - metabolism / Osteoblasts / Stem cells