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

Research output: Contribution to journalArticle

580 Citations (Scopus)

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 1 2007

Fingerprint

Chemotherapy
Stem cells
Acute Myeloid Leukemia
Bone
Stem Cells
Bone Marrow
Drug Therapy
Granulocyte Precursor Cells
Heterologous Transplantation
Interleukins
Osteoblasts
Cell death
Heterografts
Cell Cycle
Leukemia
Transplantation
Cells
Apoptosis
Cytokines
Mutation

All Science Journal Classification (ASJC) codes

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

Cite this

Ishikawa, F., Yoshida, S., Saito, Y., Hijikata, A., Kitamura, H., Tanaka, S., ... 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

Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. / Ishikawa, Fumihiko; Yoshida, Shuro; Saito, Yoriko; Hijikata, Atsushi; Kitamura, Hiroshi; Tanaka, Satoshi; Nakamura, Ryu; Tanaka, Toru; Tomiyama, Hiroko; Saito, Noriyuki; Fukata, Mitsuhiro; Miyamoto, Toshihiro; Lyons, Bonnie; Ohshima, Koichi; Uchida, Naoyuki; Taniguchi, Shuichi; Ohara, Osamu; Akashi, Koichi; Harada, Mine; Shultz, Leonard D.

In: Nature Biotechnology, Vol. 25, No. 11, 01.11.2007, p. 1315-1321.

Research output: Contribution to journalArticle

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
Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nature Biotechnology. 2007 Nov 1;25(11):1315-1321. https://doi.org/10.1038/nbt1350
Ishikawa, Fumihiko ; Yoshida, Shuro ; Saito, Yoriko ; Hijikata, Atsushi ; Kitamura, Hiroshi ; Tanaka, Satoshi ; Nakamura, Ryu ; Tanaka, Toru ; Tomiyama, Hiroko ; Saito, Noriyuki ; Fukata, Mitsuhiro ; Miyamoto, Toshihiro ; Lyons, Bonnie ; Ohshima, Koichi ; Uchida, Naoyuki ; Taniguchi, Shuichi ; Ohara, Osamu ; Akashi, Koichi ; Harada, Mine ; Shultz, Leonard D. / Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. In: Nature Biotechnology. 2007 ; Vol. 25, No. 11. pp. 1315-1321.
@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.}",
year = "2007",
month = "11",
day = "1",
doi = "10.1038/nbt1350",
language = "English",
volume = "25",
pages = "1315--1321",
journal = "Nature Biotechnology",
issn = "1087-0156",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

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.

PY - 2007/11/1

Y1 - 2007/11/1

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.

UR - http://www.scopus.com/inward/record.url?scp=35948984135&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35948984135&partnerID=8YFLogxK

U2 - 10.1038/nbt1350

DO - 10.1038/nbt1350

M3 - Article

C2 - 17952057

AN - SCOPUS:35948984135

VL - 25

SP - 1315

EP - 1321

JO - Nature Biotechnology

JF - Nature Biotechnology

SN - 1087-0156

IS - 11

ER -