International Journal of Hematology

, Volume 84, Issue 2, pp 123–127 | Cite as

Leukemia Stem Cells

  • Ling Luo
  • Zhong Chao Han
Review Article


Cancer is a multifaceted disease in which cell proliferation is no longer under normal growth control. Accumulating data have suggested the existence of cancer stem cells, a minor population of tumor cells that possess the stem cell property of selfrenewal and that are responsible for the initiation and maintenance of cancer. The knowledge of cancer stem cell biology is most advanced in research on the hematopoietic cancer, leukemia.With the identification of leukemia stem cells (LSCs) capable of repopulating nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, this body of research has led to conclusive proof for cancer stem cells.This review focuses on the biological characterization of LSCs for each type of leukemia, which has provided key insights into leukemogenic pathology and LSC-targeted therapies.

Key words

Cancer stem cells Leukemia Leukemogenesis Cancer therapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–3737.CrossRefGoogle Scholar
  2. 2.
    Passegué E, Jamieson CH, Ailles LE, Weissman IL. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A. 2003;100:11842–11849.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Blair A, Hogge DE, Ailles LE, Lansdorp PM, Sutherland HJ. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood. 1997;89:3104–3112.PubMedGoogle Scholar
  4. 4.
    Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5:738–743.CrossRefGoogle Scholar
  5. 5.
    Guzman ML, Jordan CT. Considerations for targeting malignant stem cells in leukemia. Cancer Control. 2004;11:97–104.CrossRefGoogle Scholar
  6. 6.
    Blair A, Sutherland HJ. Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117). Exp Hematol. 2000;28:660–671.CrossRefGoogle Scholar
  7. 7.
    Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14:1777–1784.CrossRefGoogle Scholar
  8. 8.
    Gilliland DG, Jordan CT, Felix CA. The molecular basis of leukemia. Hematology (Am Soc Hematol Educ Program). 2004:80–97.CrossRefGoogle Scholar
  9. 9.
    Goldman JM, Melo JV. Chronic myeloid leukemia: advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–1464.CrossRefGoogle Scholar
  10. 10.
    Holyoake TL, Jiang X, Drummond MW, et al. Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia. 2002;16:549–558.CrossRefGoogle Scholar
  11. 11.
    Clarke MF. Chronic myelogenous leukemia: identifying the hydra’s heads. N Engl J Med. 2004;351:634–636.CrossRefGoogle Scholar
  12. 12.
    Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351:657–667.CrossRefGoogle Scholar
  13. 13.
    Bhatia R, Holtz M, Niu N, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood. 2003;101:4701–4707.CrossRefGoogle Scholar
  14. 14.
    Holtz MS, Bhatia R. Effect of imatinib mesylate on chronic myelogenous leukemia hematopoietic progenitor cells. Leuk Lymphoma. 2004;45:237–245.CrossRefGoogle Scholar
  15. 15.
    Graham SM, Jorgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319–325.CrossRefGoogle Scholar
  16. 16.
    Hawkins CJ, Vaux DL. The role of the Bcl-2 family of apoptosis regulatory proteins in the immune system. Semin Immunol. 1997;9:25–33.CrossRefGoogle Scholar
  17. 17.
    Domen J. The role of apoptosis in regulating hematopoiesis and hematopoietic stem cells. Immunol Res. 2000;22:83–94.CrossRefGoogle Scholar
  18. 18.
    Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing hematopoietic stem cells. Nature. 2003;423:302–305.CrossRefGoogle Scholar
  19. 19.
    Dick JE. Stem cells: self-renewal writ in Blood. Nature. 2003;423:231–233.CrossRefGoogle Scholar
  20. 20.
    Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411:349–354.CrossRefGoogle Scholar
  21. 21.
    Bhardwaj G, Murdoch B, Wu D, et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol. 2001;2:172–180.CrossRefGoogle Scholar
  22. 22.
    Warner JK, Wang JCY, Hope KJ, Jin LQ, Dick JE. Concepts of human leukemic development. Oncogene. 2004;23:7164–7177.CrossRefGoogle Scholar
  23. 23.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–111.CrossRefGoogle Scholar
  24. 24.
    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–1851.PubMedGoogle Scholar
  25. 25.
    Lai K, Kaspar BK, Gage FH, Schaffer DV. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci. 2003;6:21–27.CrossRefGoogle Scholar
  26. 26.
    Reya T, Duncan AW,Ailles L, et al. A role for Wnt signalling in selfrenewal of haematopoietic stem cells. Nature. 2003;423:409–414.CrossRefGoogle Scholar
  27. 27.
    Van Den Berg DJ, Sharma AK, Bruno E, Hoffman R. Role of members of the Wnt gene family in human hematopoiesis. Blood. 1998;92:3189–3202.Google Scholar
  28. 28.
    Derksen PW, Tjin E, Meijer HP, et al. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc Natl Acad Sci U S A. 2004;101:6122–6127.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324–331.CrossRefGoogle Scholar
  30. 30.
    Holyoake TL, Jiang X, Drummond MW, Eaves AC, Eaves CJ. Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia. 2002;16:549–558.CrossRefGoogle Scholar
  31. 31.
    Miyamoto T, Nagafuji K, Akashi K, et al. Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. Blood. 1996;87:4789–4796.PubMedGoogle Scholar
  32. 32.
    Miyamoto T, Weissman IL, Akashi K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci U S A. 2000;97:7521–7526.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Chomel JC, Brizard F, Veinstein A, et al. Persistence of BCR-ABL genomic rearrangement in chronic myeloid leukemia patients in complete and sustained cytogenetic remission after interferon-α therapy or allogeneic bone marrow transplantation. Blood. 2000;95:404–408.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Bose S, Deninger M, Gora-Tybor J, Goldman JM, Melo JV. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood. 1998:92:3362–3367.Google Scholar
  35. 35.
    Dash AB, Williams IR, Kutok JL, et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci U S A. 2002;99:7622–7627.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Mayotte N, Roy DC, Yao J, Kroon E, Sauvageau G. Oncogenic interaction between BCR-ABL and NUP98-HOXA9 demonstrated by the use of an in vitro purging culture system. Blood. 2002;100:4177–4184.CrossRefGoogle Scholar
  37. 37.
    Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE. Purification of primitive human hematopoietic cells capable of repopulating immunedeficient mice. Proc Natl Acad Sci U S A. 1997;94:5320–5325.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood. 2003;101:3142–3149.CrossRefGoogle Scholar
  39. 39.
    Ravandi F, Estrov Z. Eradication of leukemia stem cells as a new goal of therapy in leukemia. Clin Cancer Res. 2006;12:340–344.CrossRefGoogle Scholar
  40. 40.
    Jordan CT, Guzman ML. Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene. 2004;23:7178–7187.CrossRefGoogle Scholar
  41. 41.
    Zhou S, Schuetz JD, Bunting KD, et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001;7:1028–1034.CrossRefGoogle Scholar
  42. 42.
    Costello RT, Mallet F, Gaugler B, et al. Human acute myeloid leukemia CD34R/CD38S progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res. 2000;60:4403–4411.PubMedGoogle Scholar
  43. 43.
    Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A. 2002;99:16220–16225.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ayton PM, Cleary ML. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene. 2001;20:5695–5707.CrossRefGoogle Scholar
  45. 45.
    Armstrong SA, Kung AL, Mabon ME, et al. Inhibition of FLT3 in MLL: validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 2003;3:173–183.CrossRefGoogle Scholar
  46. 46.
    Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561–566.CrossRefGoogle Scholar
  47. 47.
    O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.CrossRefGoogle Scholar
  48. 48.
    Hughes T, Branford S. Molecular monitoring of chronic myeloid leukemia. Semin Hematol. 2003;40:62–68.CrossRefGoogle Scholar
  49. 49.
    Hamann PR, Hinman LM, Hollander I, et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheam-icin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem. 2002;13:47–58.CrossRefPubMedGoogle Scholar
  50. 50.
    Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A. 2002;99:16220–16225.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood. 2005;105:4163–4169.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2006

Authors and Affiliations

  1. 1.State Key Laboratory of Experimental Hematology and National Research Center for Stem Cell Engineering and TechnologyInstitute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical CollegeTianjinChina

Personalised recommendations