Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell

Abstract

On the subject of acute myeloid leukemia (AML), there is little consensus about the target cell within the hematopoietic stem cell hierarchy that is susceptible to leukemic transformation, or about the mechanism that underlies the phenotypic, genotypic and clinical heterogeneity. Here we demonstrate that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) — termed the SCID leukemia-initiating cell, or SL-IC — possesses the differentiate and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all subtypes of AML analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34++ CD38, similar to the cell-surface phenotype of normal SCID-repopulating cells, suggesting that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation. The SL-ICs were able to differentiate in vivo into leukemic blasts, indicating that the leukemic clone is organized as a hierarchy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Fialkow, P. et al. Clonal development, stem-cell differentiation, and clinical remission in acute nonlymphocytic leukemia. N. Engl. J. Med. 317, 468–473 (1987).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  PubMed  Google Scholar 

  3. 3

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

    CAS  Google Scholar 

  4. 4

    Cline, M.J. The molecular basis of leukemia. N. Engl. J. Med. 330, 328–336 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Berger, R. et al. Cytogenetic studies on 519 consecutive de novo acute nonlympho cytic leukemias. Cancer Genet. Cytogenet. 29, 9–21 (1987).

    CAS  Article  Google Scholar 

  6. 6

    Bennett, J. et al. Proposals for the classification of the acute leukemias. Br. J. Haematol. 33, 451–458 (1976).

    CAS  Article  Google Scholar 

  7. 7

    Fialkow, P.J. et al. Acute nonlymphocytic leukemia: Heterogeneity of stem cell origin. Blood 57, 1068–1073 (1981).

    CAS  PubMed  Google Scholar 

  8. 8

    Bartram, C.R. et al. Acute myeloid leukemia: Analysis of ras gene mutations and clonality defined by polymorphic X-linked loci. Leukemia 3, 247–256 (1989).

    CAS  PubMed  Google Scholar 

  9. 9

    van Lorn, K., Hagemeijer, A., Smit, E.M. & Lowenberg, B. In situ hybridization on May-Grünwald Giemsa-stained bone marrow and blood smears of patients with hematologic disorders allows detection of cell-lineage-specific cytogenetic abnormalities. Blood 82, 884–888 (1993).

    Google Scholar 

  10. 10

    Fearon, E., Burke, P., Schiffer, C., Zehnbauer, B. & Vogelstein, B. Differentiation of leukemia cells to polymorphonuclear leukocytes in patients with acute nonlymphoblastic leukemia. N. Engl. J. Med. 315, 15–24 (1986).

    CAS  Article  Google Scholar 

  11. 11

    Feuring-Buske, M. et al. Trisomy 4 in ‘stem cell-like’ leukemic cells of a patient with AML. Leukemia 9, 1318–1320 (1995).

    CAS  PubMed  Google Scholar 

  12. 12

    Greaves, M.F. Stem cell origins of leukaemia and curability. Br. J. Cancer 67, 413–423 (1993).

    CAS  Article  Google Scholar 

  13. 13

    Keinänen, M., Griffin, J., Bloomfield, C., Machnrcki, J. & de la Chapelle, A. Clonalchromosomal abnormalities showing multiple-cell-lineage involvement in acute myeloid leukemia. N. Engl.J. Med. 318, 1153–1158 (1988).

    Article  Google Scholar 

  14. 14

    McCulloch, E.A. et al. Heterogeneity in acute myeloblastic leukemia. Leukemia 2, 38S–49S (1988).

    CAS  PubMed  Google Scholar 

  15. 15

    Haase, D. et al. Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+sub-populations. Blood 86, 2906–2912 (1995).

    CAS  PubMed  Google Scholar 

  16. 16

    Mehrotra, B. et al. Cytogenetically aberrant cells in the stem cell compartment (CD34+1in−) in acute myeloid leukemia. Blood 86, 1139–1147 (1995).

    CAS  PubMed  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

    Dick, J.E. Normal and leukemic stem cells assayed in SCID mice. Semin. Immunol. 8, 197–206 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Bhatia, M., Wang, J., Kapp, U., Bonnet, D. & Dick, J. Purification of primitive human hematopoietic cells capable of repopulating NOD/SCID mice. Proc. Natl.Acad. Sci.USA 94, 5320–5325 (1997).

    CAS  Article  Google Scholar 

  20. 20

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

    CAS  Article  Google Scholar 

  21. 21

    Larochelle, A. et al. Engraftment of immune-deficient mice with primitivehematopoietic cells from beta-thalassemia and sickle cell anemia patients:Implications for evaluating human gene therapy protocols. Hum. Mol. Genet. 4, 163–172 (1995).

    CAS  Article  Google Scholar 

  22. 22

    Wang, J., Doedens, M. & Dick, J. Primitive human hematopoietic cells are enrichedin cord blood compared to adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell (SRC) assay. Blood 89, 3919–3924 (1997).

    CAS  PubMed  Google Scholar 

  23. 23

    Porter, E. & Berry, R. The efficient design of transplantable tumor assays. Br. J. Cancer 17, 583–595 (1964).

    Article  Google Scholar 

  24. 24

    Taswell, C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J. Immunol. 126, 1614–1619 (1981).

    CAS  Google Scholar 

  25. 25

    Civin, C. et al. Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1 a cells. J. Immunol. 133, 157–165 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Terstappen, L.W.W.M., Huang, S., Safford, M., Lansdorp, P.M. & Loken, M.R. Sequential generations of hematopoietic colonies derived from single nonlineagecommitted CD34+CD38 progenitor cells. Blood 77, 1218–1227 (1991).

    CAS  Google Scholar 

  27. 27

    Terstappen, L. et al. Flow cytometry characterization of acute myeloid leukemia: IV. Comparison to the differentiation pathway of normal hematopoietic cells. Leukemia 6, 993–1000 (1992).

    CAS  Google Scholar 

  28. 28

    Cashman, J. et al. Kinetic evidence of the regeneration of multilineage hematopoiesis from primitive cells in normal human bone marrow transplanted into immunodeficient mice. Stood (in the press).

  29. 29

    Moore, M., Williams, N. & Metcalfe, D. In vitro colony formation by normal and leukemic human hematopoietic cells: Characterization of the colony-forming cells. J. Natl. Cancer Inst. 50, 603 (1974).

    Article  Google Scholar 

  30. 30

    Sutherland, H., Blair, A. & Zapf, R.W. Characterization of a hierarchy in human acute myeloid leukemia progenitor cells. Blood 87, 4754–4761 (1996).

    CAS  PubMed  Google Scholar 

  31. 31

    Craig, W., Kay, R., Cutler, R.B. & Lansdorp, P.M. Expression of Thy-1 on human hematopoietic progenitor cells. J. Exp. Med. 177, 1331–1342 (1993).

    CAS  Article  Google Scholar 

  32. 32

    Terpstra, W. et al. Long-term leukemia-initiating capacity of a CD34 subpopulation of acute myeloid leukemia. Stood 87, 2187–2194 (1996).

    CAS  Google Scholar 

  33. 33

    Sawyers, C., Gishizky, M., Quan, S., Golde, D. & Witte, O. Propagation of human blastic myeloid leukemias in the SCID mouse. Blood 79, 2089–2098 (1992).

    CAS  Google Scholar 

  34. 34

    Cesano, A. et al. The severe combined immunodeficient (SCID) mouse as a model for myeloid leukemias. Oncogene 7, 827–836 (1992).

    CAS  Google Scholar 

  35. 35

    Turhan, A.G. et al. Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia. Stood 85, 2154–2161 (1995).

    CAS  Google Scholar 

  36. 36

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

    CAS  Article  Google Scholar 

  37. 37

    Vormoor, J. et al. Immature human cord blood progenitors engraft and proliferate to high levels in immune-deficient SCID mice. Stood 83, 2489–2497 (1994).

    CAS  Google Scholar 

  38. 38

    Sirard, C. et al. Normal and leukemic SCID-repopulating cells (SRC) co-exist in the bone marrow and peripheral blood from CML patients in chronic phase while leukemic SRC are detected in blast crisis. Stood 87, 1539–1548 (1996).

    CAS  Google Scholar 

  39. 39

    Waye, J.S. & Willard, H.F. Structure, organization and sequence of alpha satellite DNA from human chromosome 17: Evidence for evolution by unequal crossing-over and ancestral pentamer repeat shared with the human X chromosome. Mol. Cell. Biol. 6, 3156–3165 (1986).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bonnet, D., Dick, J. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3, 730–737 (1997). https://doi.org/10.1038/nm0797-730

Download citation

Further reading