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.

  • Article
  • Published:

Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity

Abstract

Emerging evidence suggests cancer stem cells sustain neoplasms; however, little is understood of the normal cell initially targeted and the resultant cancer stem cells. We show here, by tracking individual human leukemia stem cells (LSCs) in nonobese diabetic–severe combined immunodeficiency mice serially transplanted with acute myeloid leukemia cells, that LSCs are not functionally homogeneous but, like the normal hematopoietic stem cell (HSC) compartment, comprise distinct hierarchically arranged LSC classes. Distinct LSC fates derived from heterogeneous self-renewal potential. Some LSCs emerged only in recipients of serial transplantation, indicating they divided rarely and underwent self-renewal rather than commitment after cell division within primary recipients. Heterogeneity in LSC self-renewal potential supports the hypothesis that they derive from normal HSCs. Furthermore, normal developmental processes are not completely abolished during leukemogenesis. The existence of multiple stem cell classes shows the need for LSC-targeted therapies.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Efficient transduction of SL-ICs.
Figure 2: Differential characteristics of human grafts in NOD-SCID mice transplanted with normal cord blood or AML cells.
Figure 3: In vivo kinetic activity of individual SL-IC clones in NOD-SCID mice as determined by integration site analysis.
Figure 4: Heterogeneous self-renewal capacity of transduced SL-ICs.

Similar content being viewed by others

References

  1. Dick, J.E. Breast cancer stem cells revealed. Proc. Natl. Acad. Sci. USA 100, 3547–3549 (2003).

    Article  CAS  Google Scholar 

  2. McCulloch, E. Stem cells in normal and leukemic hemopoiesis (Henry Stratton Lecture). Blood 62, 1–13 (1983).

    CAS  PubMed  Google Scholar 

  3. Griffin, J. & Löwenberg, B. Clonogenic cells in acute myeloblastic leukemia. Blood 68, 1185–1195 (1986).

    CAS  PubMed  Google Scholar 

  4. Larochelle, A. et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nat. Med. 2, 1329–1337 (1996).

    Article  CAS  Google Scholar 

  5. Kamel-Reid, S. & Dick, J.E. Engraftment of immune-deficient mice with human hematopoietic stem cells. Science 242, 1706–1709 (1988).

    Article  CAS  Google Scholar 

  6. Kamel-Reid, S. et al. A model of human acute lymphoblastic leukemia in immune-deficient SCID mice. Science 246, 1597–1600 (1989).

    Article  CAS  Google Scholar 

  7. Lapidot, T. et al. Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in scid mice. Science 255, 1137–1141 (1992).

    Article  CAS  Google Scholar 

  8. 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 

  9. Ailles, L.E., Gerhard, B., Kawagoe, H. & Hogge, D.E. Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice. Blood 94, 1761–1772 (1999).

    CAS  PubMed  Google Scholar 

  10. Rombouts, W.J., Martens, A.C. & Ploemacher, R.E. Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model. Leukemia 14, 889–897 (2000).

    Article  CAS  Google Scholar 

  11. Bhatia, M., Wang, J.C.Y., Kapp, U., Bonnet, D. & Dick, J.E. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc. Natl. Acad. Sci. USA 94, 5320–5325 (1997).

    Article  CAS  Google Scholar 

  12. Conneally, E., Cashman, J., Petzer, A. & Eaves, C. Expansion in vitro of transplantable human cord blood stem cells demonstrated using a quantitative assay of their lympho-myeloid repopulating activity in nonobese diabetic-scid/scid mice. Proc. Natl. Acad. Sci. USA 94, 9836–9841 (1997).

    Article  CAS  Google Scholar 

  13. 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 

  14. Blair, A., Hogge, D.E., Ailles, L.E., Lansdorp, P.M. & Sutherland, H.J. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 89, 3104–3112 (1997).

    CAS  PubMed  Google Scholar 

  15. Jordan, C.T. et al. The interleukin-3 receptor α chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14, 1777–1784 (2000).

    Article  CAS  Google Scholar 

  16. Blair, A., Hogge, D.E. & Sutherland, H.J. Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34+/CD71−/HLA-DR. Blood 92, 4325–4335 (1998).

    CAS  PubMed  Google Scholar 

  17. Brendel, C. et al. Detection of cytogenetic aberrations both in CD90 (Thy-1)-positive and (Thy-1)-negative stem cell (CD34) subfractions of patients with acute and chronic myeloid leukemias. Leukemia 13, 1770–1775 (1999).

    Article  CAS  Google Scholar 

  18. Dick, J.E. Stem cells: Self-renewal writ in blood. Nature 423, 231–233 (2003).

    Article  CAS  Google Scholar 

  19. Guenechea, G., Gan, O.I., Dorrell, C. & Dick, J.E. Distinct classes of human stem cells that differ in proliferative and self-renewal potential. Nat. Immunol. 2, 75–82 (2001).

    Article  CAS  Google Scholar 

  20. Ailles, L.E., Humphries, R.K., Thomas, T.E. & Hogge, D.E. Retroviral marking of acute myelogenous leukemia progenitors that initiate long-term culture and growth in immunodeficient mice. Exp. Hematol. 27, 1609–1620 (1999).

    Article  CAS  Google Scholar 

  21. Guzman, M.L. et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98, 2301–2307 (2001).

    Article  CAS  Google Scholar 

  22. Terpstra, W. et al. Fluorouracil selectively spares acute myeloid leukemia cells with long-term growth abilities in immunodeficient mice and in culture. Blood 88, 1944–1950 (1996).

    CAS  PubMed  Google Scholar 

  23. Mazurier, F., Gan, O., McKenzie, J., Doedens, M. & Dick, J. Lentivector-mediated clonal tracking reveals intrinsic heterogeneity in the human hematopoietic stem cell compartment and culture-induced stem cell impairment. Blood 103, 545–552 (2004).

    Article  CAS  Google Scholar 

  24. Miyoshi, H., Smith, K.A., Mosier, D.E., Verma, I.M. & Torbett, B.E. Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors. Science 283, 682–686 (1999).

    Article  CAS  Google Scholar 

  25. Guenechea, G. et al. Transduction of human CD34+ CD38− bone marrow and cord blood-derived SCID-repopulating cells with third-generation lentiviral vectors. Mol. Ther. 1, 566–573 (2000).

    Article  CAS  Google Scholar 

  26. Terpstra, W. et al. Conditions for engraftment of human acute myeloid leukemia (AML) in SCID mice. Leukemia 9, 1573–1577 (1995).

    CAS  PubMed  Google Scholar 

  27. Guan, Y., Gerhard, B. & Hogge, D.E. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood 101, 3142–3149 (2003).

    Article  CAS  Google Scholar 

  28. Till, J.E. & McCulloch, E.A. Hemopoietic stem cell differentiation. Biochim. Biophys. Acta 605, 431–459 (1980).

    CAS  PubMed  Google Scholar 

  29. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukemic stem cells. Nature 423, 455–460 (2003).

    Article  Google Scholar 

  30. Greaves, M. Differentiation-linked leukemogenesis in lymphocytes. Science 234, 697–704 (1986).

    Article  CAS  Google Scholar 

  31. Kamel-Reid, S. et al. Bone marrow from children in relapse with pre-B acute lymphoblastic leukemia proliferates and disseminates rapidly in scid mice. Blood 78, 2973–2981 (1991).

    CAS  PubMed  Google Scholar 

  32. Guzman, M.L. et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc. Natl. Acad. Sci. USA 99, 16220–16225 (2002).

    Article  CAS  Google Scholar 

  33. Al-Hajj, M., Wicha, M., Morrison, S.J. & Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  Google Scholar 

  34. Reya, T., Morrison, S.J., Clarke, M.F. & Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  Google Scholar 

  35. Singh, S. et al. Identification of a cancer stem cell in human brain tumours. Cancer Res. 63, 5281–5288 (2003).

    Google Scholar 

  36. Marx, J. Cancer research. Mutant stem cells may seed cancer. Science 301, 1308–1310 (2003).

    Article  CAS  Google Scholar 

  37. Bernards, R. & Weinberg, R.A. A progression puzzle. Nature 418, 823 (2002).

    Article  CAS  Google Scholar 

  38. Follenzi, A., Ailles, L.E., Bakovic, S., Geuna, M. & Naldini, L. Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences. Nat. Genet. 25, 217–222 (2000).

    Article  CAS  Google Scholar 

  39. Guenechea, G. et al. Delayed engraftment of nonobese diabetic/severe combined immunodeficient mice transplanted with ex vivo-expanded human CD34+ cord blood cells. Blood 93, 1097–1105 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Minden (Princess Margaret Hospital, Toronto, Ontario, Canada) and E. Warren (Hutchinson Cancer Center, Seattle, Washington, USA) for providing AML samples; and members of the Dick lab, M. Minden, N. Iscove and C. Jordan for critical comments on the manuscript. Supported by the Leukemia Research Fund of Canada (L.J.) and Canadian Institutes for Health Research (L.J. and K.H.); and The Stem Cell Network of the National Centres of Excellence, National Cancer Institute of Canada and Canadian Cancer Society, Canadian Genetic Diseases Network of the National Centres of Excellence, Canadian Institutes for Health Research, and Canada Research (J.E.D.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John E Dick.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hope, K., Jin, L. & Dick, J. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5, 738–743 (2004). https://doi.org/10.1038/ni1080

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1080

This article is cited by

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