Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Biotechnology volume 25, pages 1315–1321 (2007)Cite this article

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

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Self-renewing, long-term engrafting primary human LS cells reside exclusively within the hCD34+hCD38− population.
Figure 2: Primary human LS cells home to and engraft within the bone-marrow osteoblast-rich area, suppressing normal murine hematopoiesis.
Figure 3: Primary hCD34+hCD38− LS cells within the endosteal region exhibit relative resistance to Ara-C induced apoptosis.
Figure 4: Global gene expression profiling of primary human AML and recipient mouse bone-marrow identifies LS cell–specific transcripts.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Passegue, E., Jamieson, C.H., Ailles, L.E. & Weissman, I.L. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc. Natl. Acad. Sci. USA 100 Suppl 1. 11842–11849 (2003).

    Article  CAS  Google Scholar 

  2. Hope, K.J., Jin, L. & Dick, J.E. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat. Immunol. 5, 738–743 (2004).

    Article  CAS  Google Scholar 

  3. Jordan, C.T. & Guzman, M.L. Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene 23, 7178–7187 (2004).

    Article  CAS  Google Scholar 

  4. Ishikawa, F. et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood 106, 1565–1573 (2005).

    Article  CAS  Google Scholar 

  5. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    Article  CAS  Google Scholar 

  6. Bonnet, D. & Dick, J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).

    Article  CAS  Google Scholar 

  7. Ailles, L.E., Gerhard, B. & Hogge, D.E. Detection and characterization of primitive malignant and normal progenitors in patients with acute myelogenous leukemia using long-term coculture with supportive feeder layers and cytokines. Blood 90, 2555–2564 (1997).

    CAS  PubMed  Google Scholar 

  8. Lumkul, R. et al. Human AML cells in NOD/SCID mice: engraftment potential and gene expression. Leukemia 16, 1818–1826 (2002).

    Article  CAS  Google Scholar 

  9. Feuring-Buske, M. et al. Improved engraftment of human acute myeloid leukemia progenitor cells in beta 2-microglobulin-deficient NOD/SCID mice and in NOD/SCID mice transgenic for human growth factors. Leukemia 17, 760–763 (2003).

    Article  CAS  Google Scholar 

  10. Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2, 223–238 (1995).

    Article  CAS  Google Scholar 

  11. Shultz, L.D. et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J. Immunol. 154, 180–191 (1995).

    CAS  Google Scholar 

  12. Christianson, S.W. et al. Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice. J. Immunol. 158, 3578–3586 (1997).

    CAS  PubMed  Google Scholar 

  13. Shultz, L.D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005).

    Article  CAS  Google Scholar 

  14. Ninomiya, M. et al. Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice. Leukemia 21, 136–142 (2007).

    Article  CAS  Google Scholar 

  15. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).

    Article  CAS  Google Scholar 

  16. Calvi, L.M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    Article  CAS  Google Scholar 

  17. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

    Article  CAS  Google Scholar 

  18. Guzman, M.L. et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105, 4163–4169 (2005).

    Article  CAS  Google Scholar 

  19. Taussig, D.C. et al. Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106, 4086–4092 (2005).

    Article  CAS  Google Scholar 

  20. Charrad, R.S. et al. Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia. Nat. Med. 5, 669–676 (1999).

    Article  CAS  Google Scholar 

  21. Jin, L., Hope, K.J., Zhai, Q., Smadja-Joffe, F. & Dick, J.E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 12, 1167–1174 (2006).

    Article  Google Scholar 

  22. Krause, D.S., Lazarides, K., von Andrian, U.H. & Van Etten, R.A. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat. Med. 12, 1175–1180 (2006).

    Article  CAS  Google Scholar 

  23. Cursi, S. et al. Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO J. 25, 1895–1905 (2006).

    Article  CAS  Google Scholar 

  24. Janes, S.M. & Watt, F.M. New roles for integrins in squamous-cell carcinoma. Nat. Rev. Cancer 6, 175–183 (2006).

    Article  CAS  Google Scholar 

  25. Ji, P. et al. Cyclin A1, the alternative A-type cyclin, contributes to G1/S cell cycle progression in somatic cells. Oncogene 24, 2739–2744 (2005).

    Article  CAS  Google Scholar 

  26. Tanner, S.M. et al. BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc. Natl. Acad. Sci. USA 98, 13901–13906 (2001).

    Article  CAS  Google Scholar 

  27. Nilsson, S.K., Johnston, H.M. & Coverdale, J.A. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 97, 2293–2299 (2001).

    Article  CAS  Google Scholar 

  28. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  Google Scholar 

  29. Suzuki, R. & Shimodaira, H. Pvclust: an R package for assessing the uncertainty in hierarchical clustering. Bioinformatics 22, 1540–1542 (2006).

    Article  CAS  Google Scholar 

  30. Culhane, A.C., Thioulouse, J., Perriere, G. & Higgins, D.G. MADE4: an R package for multivariate analysis of gene expression data. Bioinformatics 21, 2789–2790 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama, 230-0045, Japan

    Fumihiko Ishikawa, Shuro Yoshida & Yoriko Saito

  2. Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama, 230-0045, Japan

    Atsushi Hijikata, Hiroshi Kitamura & Osamu Ohara

  3. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan

    Fumihiko Ishikawa, Shuro Yoshida, Noriyuki Saito, Mitsuhiro Fukata & Mine Harada

  4. Center for Cellular and Molecular Medicine, Kyushu University Hospital, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan

    Toshihiro Miyamoto & Koichi Akashi

  5. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Yoriko Saito

  6. Nippon Becton Dickinson Company, 4-15-1 Akasaka Minato-ku, Tokyo, 107-0052, Japan

    Satoshi Tanaka & Hiroko Tomiyama

  7. Carl Zeiss, 22 Honshio-cho, Shinjuku-ku, Tokyo, 160-0003, Japan

    Ryu Nakamura & Toru Tanaka

  8. The Jackson Laboratory, 600 Main Street, Bar Harbor, 04609, Maine, USA

    Bonnie Lyons & Leonard D Shultz

  9. First Department of Pathology, Kurume University School of Medicine, 67 Asahi-cho, Kurume, 830-0011, Japan

    Koichi Ohshima

  10. Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon Minato-ku, Tokyo, 105-8470, Japan

    Naoyuki Uchida & Shuichi Taniguchi

  11. Department of Human Genome Technology, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, 290-0818, Japan

    Osamu Ohara

  12. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Koichi Akashi

Authors
  1. Fumihiko Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuro Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoriko Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Atsushi Hijikata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroshi Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryu Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toru Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroko Tomiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Noriyuki Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mitsuhiro Fukata
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Toshihiro Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Bonnie Lyons
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Koichi Ohshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Naoyuki Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shuichi Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Osamu Ohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Koichi Akashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Mine Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Leonard D Shultz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.I., overall experimental design, transplantation, data analysis, manuscript preparation and discussion; S.Y. transplantation and data analysis; Y.S. overall experimental design, data analysis, statistical analysis, manuscript preparation and discussion; A.H., microarray analysis; H.K., microarray analysis; S.T., flow cytometry; R.N., confocal imaging; T.T., confocal imaging; H.T., flow cytometry; N.S., data analysis; M.F., data analysis; T.M., discussion; B.L., data analysis; K.O., histological analysis; N.U., discussion; S.T., discussion; O.O., microarray analysis and discussion; K.A., discussion; M.H., discussion; L.D.S., discussion.

Corresponding author

Correspondence to Fumihiko Ishikawa.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 4088 kb)

Supplementary Table 1

Serial engraftment of sorted hCD34+hCD38- AML cells. (XLS 53 kb)

Supplementary Table 2

Gene set enrichment analysis identifies genes consistently enriched in hCD34+hCD38− compared with hCD34+hCD38+ cells. (XLS 35 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ishikawa, F., Yoshida, S., Saito, Y. et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25, 1315–1321 (2007). https://doi.org/10.1038/nbt1350

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt1350

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing