Letter abstract
Nature Biotechnology 25, 1315 - 1321 (2007)
Published online: 21 October 2007 | doi:10.1038/nbt1350
Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region
Fumihiko Ishikawa1,3, Shuro Yoshida1,3, Yoriko Saito1,5, Atsushi Hijikata2, Hiroshi Kitamura2, Satoshi Tanaka6, Ryu Nakamura7, Toru Tanaka7, Hiroko Tomiyama6, Noriyuki Saito3, Mitsuhiro Fukata3, Toshihiro Miyamoto4, Bonnie Lyons8, Koichi Ohshima9, Naoyuki Uchida10, Shuichi Taniguchi10, Osamu Ohara2,11, Koichi Akashi4,12, Mine Harada3 & Leonard D Shultz8
Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells1, 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)2r
null mice carrying a complete null mutation of the cytokine c upon the SCID background4. 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.
- Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama 230-0045 Japan.
- Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama 230-0045 Japan.
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582 Japan.
- Center for Cellular and Molecular Medicine, Kyushu University Hospital, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582 Japan.
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
- Nippon Becton Dickinson Company, 4-15-1 Akasaka Minato-ku, Tokyo 107-0052 Japan.
- Carl Zeiss, 22 Honshio-cho, Shinjuku-ku, Tokyo 160-0003 Japan.
- The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
- First Department of Pathology, Kurume University School of Medicine, 67 Asahi-cho, Kurume 830-0011 Japan.
- Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon Minato-ku, Tokyo 105-8470 Japan.
- Department of Human Genome Technology, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu 290-0818 Japan.
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.
Correspondence to: Fumihiko Ishikawa1,3 e-mail: f_ishika@rcai.riken.jp
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