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

doi:10.1038/nbt1350

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)2rγ^null 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 language	English
Pages (from-to)	1315-1321
Number of pages	7
Journal	Nature Biotechnology
Volume	25
Issue number	11
DOIs	https://doi.org/10.1038/nbt1350
Publication status	Published - Nov 2007

All Science Journal Classification (ASJC) codes

Applied Microbiology and Biotechnology
Bioengineering
Molecular Medicine
Biotechnology
Biomedical Engineering

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nbt1350

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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

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, LD 2007, 'Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region', Nature Biotechnology, vol. 25, no. 11, pp. 1315-1321. https://doi.org/10.1038/nbt1350

@article{24116f491e0f4a94ade0c8b7fa1b02a1,

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

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.",

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

note = "Funding Information: We thank T. Kanabayashi for the preparation of immunohistochemical staining; N. Aoki for assistance with bone sections; N. Suzuki for technical assistance; N. Kinukawa for assistance with statistical analysis; and F. Ishidate (Carl Zeiss) for assistance with microscopy. This work was supported by the Japan Ministry of Education, Culture, Sports, Science and Technology grant to F.I. and by the US National Institutes of Health grant to L.D.S.",

year = "2007",

month = nov,

doi = "10.1038/nbt1350",

language = "English",

volume = "25",

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T1 - Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region

AU - Ishikawa, Fumihiko

AU - Yoshida, Shuro

AU - Saito, Yoriko

AU - Hijikata, Atsushi

AU - Kitamura, Hiroshi

AU - Tanaka, Satoshi

AU - Nakamura, Ryu

AU - Tanaka, Toru

AU - Tomiyama, Hiroko

AU - Saito, Noriyuki

AU - Fukata, Mitsuhiro

AU - Miyamoto, Toshihiro

AU - Lyons, Bonnie

AU - Ohshima, Koichi

AU - Uchida, Naoyuki

AU - Taniguchi, Shuichi

AU - Ohara, Osamu

AU - Akashi, Koichi

AU - Harada, Mine

AU - Shultz, Leonard D.

N1 - Funding Information: We thank T. Kanabayashi for the preparation of immunohistochemical staining; N. Aoki for assistance with bone sections; N. Suzuki for technical assistance; N. Kinukawa for assistance with statistical analysis; and F. Ishidate (Carl Zeiss) for assistance with microscopy. This work was supported by the Japan Ministry of Education, Culture, Sports, Science and Technology grant to F.I. and by the US National Institutes of Health grant to L.D.S.

PY - 2007/11

Y1 - 2007/11

N2 - 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.

AB - 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.

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

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