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

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

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Abstract

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)2rγnull mice carrying a complete null mutation of the cytokine γc 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.

Original languageEnglish
Pages (from-to)1315-1321
Number of pages7
JournalNature Biotechnology
Volume25
Issue number11
DOIs
Publication statusPublished - Nov 2007

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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    Ishikawa, F., Yoshida, S., Saito, Y., Hijikata, A., Kitamura, H., Tanaka, S., Nakamura, R., Tanaka, T., Tomiyama, H., Saito, N., Fukata, M., Miyamoto, T., Lyons, B., Ohshima, K., Uchida, N., Taniguchi, S., Ohara, O., Akashi, K., Harada, M., & Shultz, L. D. (2007). Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nature Biotechnology, 25(11), 1315-1321. https://doi.org/10.1038/nbt1350