Stem Cells in Leukemia and Other Hematological Malignancies

  • Mhairi Copland
  • Alison M. Michie
  • Tessa L. Holyoake


Leukemia was the first malignant condition in which cancer stem cells were described. Leukemia stem cells (LSCs) have now been described in a number of different types of leukemia and are currently a major focus of research interest. LSCs are an important target for treatment of leukemia, and failure to eradicate these very primitive cancer cells is a common cause of leukemia relapse. Therefore, improved understanding of the biology of LSCs and the differences between normal hematopoietic and leukemic stem cells is likely to lead to the development of novel therapeutic strategies and improvements in leukemia therapy and patient survival.


Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Chronic Myeloid Leukemia Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abrahamsson, A., Geron, I., Gotlib, J., Dao, K.-H., Giles, F., Newton, I., Kavalerchik, E., Durocher, J., Creusot, R., Karimi, M., Jones, C., Zehnder, J., Keating, A., Negrin, R., Weissman, I. L. and Jamieson, C. H. M. 2007. Missplicing of glycogen synthase kinase 3β: a potential mechanism of blast crisis chronic myeloid leukemia stem cell generation. Blood 110:238a–9a.Google Scholar
  2. Argiropoulos, B. and Humphries, R. K. 2007. Hox genes in hematopoiesis and leukemogenesis. Oncogene 26:6766–76.PubMedCrossRefGoogle Scholar
  3. Artavanis-Tsakonas, S., Rand, M. D. and Lake, R. J. 1999. Notch signaling: cell fate control and signal integration in development. Science 284:770–6.PubMedCrossRefGoogle Scholar
  4. Aster, J. C., Pear, W. S. and Blacklow, S. C. 2008. Notch signaling in leukemia. Annu Rev Pathol 3:587–613.PubMedCrossRefGoogle Scholar
  5. Attar, E. C., Deangelo, D. J., Supko, J. G., D'Amato, F., Zahrieh, D., Sirulnik, A., Wadleigh, M., Ballen, K. K., McAfee, S., Miller, K. B., Levine, J., Galinsky, I., Trehu, E. G., Schenkein, D., Neuberg, D., Stone, R. M. and Amrein, P. C. 2008. Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with acute myelogenous leukemia. Clin Cancer Res 14:1446–54.PubMedCrossRefGoogle Scholar
  6. Bartram, C. R., de Klein, A., Hagemeijer, A., van Agthoven, T., Geurts van Kessel, A., Bootsma, D., Grosveld, G., Ferguson-Smith, M. A., Davies, T., Stone, M., et al. 1983. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 306:277–80.Google Scholar
  7. Blair, A. and Sutherland, H. J. 2000. Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117). Exp Hematol 28:660–71.PubMedCrossRefGoogle Scholar
  8. Blair, A., Hogge, D. E., Ailles, L. E., Lansdorp, P. M. and Sutherland, H. J. 1997. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 89:3104–12.PubMedGoogle Scholar
  9. Blair, A., Hogge, D. E. and Sutherland, H. J. 1998. Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(-)/HLA-DR. Blood 92:4325–35.PubMedGoogle Scholar
  10. Bonnet, D. and Dick, J. E. 1997. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–7.PubMedCrossRefGoogle Scholar
  11. Borrow, J., Shearman, A. M., Stanton, V. P., Jr., Becher, R., Collins, T., Williams, A. J., Dube, I., Katz, F., Kwong, Y. L., Morris, C., Ohyashiki, K., Toyama, K., Rowley, J. and Housman, D. E. 1996. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 12:159–67.PubMedCrossRefGoogle Scholar
  12. Branford, S., Rudzki, Z., Grigg, A., Seymour, J. F., Taylor, K., Browett, P., Schwarer, A., Bradstock, K., Arthur, C., Durrant, S., Ma, D., Joske, D., Lynch, K. and Hughes, T. 2004. BCR-ABL levels continue to decrease up to 42 months after commencement of standard dose imatinib in patients with newly diagnosed chronic phase CML who achieve a molecular response. Blood 104:82a.CrossRefGoogle Scholar
  13. Brummendorf, T. H., Holyoake, T. L., Rufer, N., Barnett, M. J., Schulzer, M., Eaves, C. J., Eaves, A. C. and Lansdorp, P. M. 2000. Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood 95:1883–90.PubMedGoogle Scholar
  14. Bruserud, O., Stapnes, C., Ersvaer, E., Gjertsen, B. T. and Ryningen, A. 2007. Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell. Curr Pharm Biotechnol 8:388–400.PubMedCrossRefGoogle Scholar
  15. Castor, A., Nilsson, L., Astrand-Grundstrom, I., Buitenhuis, M., Ramirez, C., Anderson, K., Strombeck, B., Garwicz, S., Bekassy, A. N., Schmiegelow, K., Lausen, B., Hokland, P., Lehmann, S., Juliusson, G., Johansson, B. and Jacobsen, S. E. 2005. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 11:630–7.PubMedCrossRefGoogle Scholar
  16. Chen, Y. J., Sims-Mourtada, J., Izzo, J. and Chao, K. S. 2007. Targeting the hedgehog pathway to mitigate treatment resistance. Cell Cycle 6:1826–30.PubMedCrossRefGoogle Scholar
  17. Christ, O., Lucke, K., Imren, S., Leung, K., Hamilton, M., Eaves, A., Smith, C. and Eaves, C. 2007. Improved purification of hematopoietic stem cells based on their elevated aldehyde dehydrogenase activity. Haematologica 92:1165–72.PubMedCrossRefGoogle Scholar
  18. Cobaleda, C., Gutierrez-Cianca, N., Perez-Losada, J., Flores, T., Garcia-Sanz, R., Gonzalez, M. and Sanchez-Garcia, I. 2000. A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia. Blood 95:1007–13.PubMedGoogle Scholar
  19. Coiffier, B., Lepage, E., Briere, J., Herbrecht, R., Tilly, H., Bouabdallah, R., Morel, P., Van Den Neste, E., Salles, G., Gaulard, P., Reyes, F., Lederlin, P. and Gisselbrecht, C. 2002. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–42.PubMedCrossRefGoogle Scholar
  20. Copland, M., Hamilton, A., Elrick, L. J., Baird, J. W., Allan, E. K., Jordanides, N., Barow, M., Mountford, J. C. and Holyoake, T. L. 2006. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction. Blood 107:4532–9.PubMedCrossRefGoogle Scholar
  21. Copland, M., Pellicano, F., Richmond, L., Allan, E. K., Hamilton, A., Lee, F. Y., Weinmann, R. and Holyoake, T. L. 2008. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood 111:2843–53.PubMedCrossRefGoogle Scholar
  22. Cortes, J., O'Brien, S. and Kantarjian, H. 2004. Discontinuation of imatinib therapy after achieving a molecular response. Blood 104:2204–5.PubMedCrossRefGoogle Scholar
  23. Coulombel, L. 2004. Identification of hematopoietic stem/progenitor cells: strength and drawbacks of functional assays. Oncogene 23:7210–22.PubMedCrossRefGoogle Scholar
  24. Coulombel, L., Eaves, A. C. and Eaves, C. J. 1983. Enzymatic treatment of long-term human marrow cultures reveals the preferential location of primitive hemopoietic progenitors in the adherent layer. Blood 62:291–7.PubMedGoogle Scholar
  25. Cox, C. V., Evely, R. S., Oakhill, A., Pamphilon, D. H., Goulden, N. J. and Blair, A. 2004. Characterization of acute lymphoblastic leukemia progenitor cells. Blood 104:2919–25.PubMedCrossRefGoogle Scholar
  26. Cozzio, A., Passegue, E., Ayton, P. M., Karsunky, H., Cleary, M. L. and Weissman, I. L. 2003. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 17:3029–35.PubMedCrossRefGoogle Scholar
  27. Damle, R. N., Wasil, T., Fais, F., Ghiotto, F., Valetto, A., Allen, S. L., Buchbinder, A., Budman, D., Dittmar, K., Kolitz, J., Lichtman, S. M., Schulman, P., Vinciguerra, V. P., Rai, K. R., Ferrarini, M. and Chiorazzi, N. 1999. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–7.PubMedGoogle Scholar
  28. DeAngelo, D. J., Stone, R. M., Silverman, L. B., Stock, W., Attar, E. C., Fearen, I., Dallob, A., Matthews, C., Stone, J., Freedman, S. J. and Aster, J. 2006. A phase 1 clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol 24:6585.Google Scholar
  29. Dierks, C., Beigi, R., Stegert, M., Zirlik, K., Schmitt-Graeff, A., Veelken, H. and Warmuth, M. 2007. Expansion of BCR-ABL positive leukemic stem cells is dependent on Hedgehog pathway activation. Blood 110:990aGoogle Scholar
  30. Dikmen, Z. G., Gellert, G. C., Jackson, S., Gryaznov, S., Tressler, R., Dogan, P., Wright, W. E. and Shay, J. W. 2005. In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor. Cancer Res 65:7866–73.PubMedGoogle Scholar
  31. Druker, B. J., Tamura, S., Buchdunger, E., Ohno, S., Segal, G. M., Fanning, S., Zimmermann, J. and Lydon, N. B. 1996. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–6.PubMedCrossRefGoogle Scholar
  32. Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E., Ford, J. M., Lydon, N. B., Kantarjian, H., Capdeville, R., Ohno-Jones, S. and Sawyers, C. L. 2001. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–7.PubMedCrossRefGoogle Scholar
  33. Druker, B. J., Guilhot, F., O'Brien, S. G., Gathmann, I., Kantarjian, H., Gattermann, N., Deininger, M. W., Silver, R. T., Goldman, J. M., Stone, R. M., Cervantes, F., Hochhaus, A., Powell, B. L., Gabrilove, J. L., Rousselot, P., Reiffers, J., Cornelissen, J. J., Hughes, T., Agis, H., Fischer, T., Verhoef, G., Shepherd, J., Saglio, G., Gratwohl, A., Nielsen, J. L., Radich, J. P., Simonsson, B., Taylor, K., Baccarani, M., So, C., Letvak, L. and Larson, R. A. 2006. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–17.PubMedCrossRefGoogle Scholar
  34. Early Breast Cancer Trialists' Collaborative Group. 1998. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 351:1451–67.Google Scholar
  35. Eaves, A. C., Barnett, M. J., Ponchio, L., Cashman, J. D., Petzer, A. L. and Eaves, C. J. 1998. Differences between normal and CML stem cells: potential targets for clinical exploitation. Stem Cells 16 Suppl 1:77–83; discussion 89.PubMedGoogle Scholar
  36. Fialkow, P. J., Jacobson, R. J. and Papayannopoulou, T. 1977. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med 63:125–30.PubMedCrossRefGoogle Scholar
  37. Ford, C. E., Hamerton, J. L., Barnes, D. W. and Loutit, J. F. 1956. Cytological identification of radiation-chimaeras. Nature 177:452–4.PubMedCrossRefGoogle Scholar
  38. Foster, A. E., Dotti, G., Lu, A., Andreeff, M., Goodell, M., Rooney, C. M. and Brenner, M. K. 2006. Immune responses are induced against side-population B-CLL “stem cells” by patient vaccination with hCD40/IL2 gene modified tumor cells. Blood 108:721a–2a.Google Scholar
  39. Golub, T. R., Slonim, D. K., Tamayo, P., Huard, C., Gaasenbeek, M., Mesirov, J. P., Coller, H., Loh, M. L., Downing, J. R., Caligiuri, M. A., Bloomfield, C. D. and Lander, E. S. 1999. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286:531–7.PubMedCrossRefGoogle Scholar
  40. Gorre, M. E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P. N. and Sawyers, C. L. 2001. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–80.PubMedCrossRefGoogle Scholar
  41. Graham, S. M., Jorgensen, H. G., Allan, E., Pearson, C., Alcorn, M. J., Richmond, L. and Holyoake, T. L. 2002. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99:319–25.PubMedCrossRefGoogle Scholar
  42. Graham, S. M., Vass, J. K., Holyoake, T. L. and Graham, G. J. 2007. Transcriptional analysis of quiescent and proliferating CD34+ human haemopoietic cells from normal and CML sources. Stem Cells 25:3111–20.Google Scholar
  43. Groffen, J., Stephenson, J. R., Heisterkamp, N., de Klein, A., Bartram, C. R. and Grosveld, G. 1984. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36:93–9.PubMedCrossRefGoogle Scholar
  44. Guenechea, G., Gan, O. I., Dorrell, C. and Dick, J. E. 2001. Distinct classes of human stem cells that differ in proliferative and self-renewal potential. Nat Immunol 2:75–82.PubMedCrossRefGoogle Scholar
  45. Guzman, M. L., Neering, S. J., Upchurch, D., Grimes, B., Howard, D. S., Rizzieri, D. A., Luger, S. M. and Jordan, C. T. 2001. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98:2301–7.PubMedCrossRefGoogle Scholar
  46. Guzman, M. L., Swiderski, C. F., Howard, D. S., Grimes, B. A., Rossi, R. M., Szilvassy, S. J. and Jordan, C. T. 2002. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci USA 99:16220–5.PubMedCrossRefGoogle Scholar
  47. Guzman, M. L., Rossi, R. M., Karnischky, L., Li, X., Peterson, D. R., Howard, D. S. and Jordan, C. T. 2005. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105:4163–9.PubMedCrossRefGoogle Scholar
  48. Guzman, M. L., Li, X., Corbett, C. A., Rossi, R. M., Bushnell, T., Liesveld, J. L., Hebert, J., Young, F. and Jordan, C. T. 2007a. Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8). Blood 110:4436–44.Google Scholar
  49. Guzman, M. L., Rossi, R. M., Neelakantan, S., Li, X., Corbett, C. A., Hassane, D. C., Becker, M. W., Bennett, J. M., Sullivan, E., Lachowicz, J. L., Vaughan, A., Sweeney, C. J., Matthews, W., Carroll, M., Liesveld, J. L., Crooks, P. A. and Jordan, C. T. 2007b. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 110:4427–35.Google Scholar
  50. Hamblin, T. J., Davis, Z., Gardiner, A., Oscier, D. G. and Stevenson, F. K. 1999. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848–54.PubMedGoogle Scholar
  51. Hatano, M., Roberts, C. W., Minden, M., Crist, W. M. and Korsmeyer, S. J. 1991. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science 253:79–82.PubMedCrossRefGoogle Scholar
  52. Hogge, D. E., Lansdorp, P. M., Reid, D., Gerhard, B. and Eaves, C. J. 1996. Enhanced detection, maintenance, and differentiation of primitive human hematopoietic cells in cultures containing murine fibroblasts engineered to produce human steel factor, interleukin-3, and granulocyte colony-stimulating factor. Blood 88:3765–73.PubMedGoogle Scholar
  53. Holyoake, T., Jiang, X., Eaves, C. and Eaves, A. 1999a. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 94:2056–64.PubMedGoogle Scholar
  54. Holyoake, T. L., Nicolini, F. E. and Eaves, C. J. 1999b. Functional differences between transplantable human hematopoietic stem cells from fetal liver, cord blood, and adult marrow. Exp Hematol 27:1418–27.PubMedCrossRefGoogle Scholar
  55. Holyoake, T. L., Jiang, X., Jorgensen, H. G., Graham, S., Alcorn, M. J., Laird, C., Eaves, A. C. and Eaves, C. J. 2001. Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood 97:720–8.PubMedCrossRefGoogle Scholar
  56. Hong, D., Gupta, R., Ancliff, P., Atzberger, A., Brown, J., Soneji, S., Green, J., Colman, S., Piacibello, W., Buckle, V., Tsuzuki, S., Greaves, M. and Enver, T. 2008. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 319:336–9.PubMedCrossRefGoogle Scholar
  57. Hope, K. J., Jin, L. and Dick, J. E. 2004. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5:738–43.PubMedCrossRefGoogle Scholar
  58. Hosen, N., Park, C. Y., Tatsumi, N., Oji, Y., Sugiyama, H., Gramatzki, M., Krensky, A. M. and Weissman, I. L. 2007. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci USA 104:11008–13.PubMedCrossRefGoogle Scholar
  59. Hughes, T. P., Kaeda, J., Branford, S., Rudzki, Z., Hochhaus, A., Hensley, M. L., Gathmann, I., Bolton, A. E., van Hoomissen, I. C., Goldman, J. M. and Radich, J. P. 2003. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423–32.PubMedCrossRefGoogle Scholar
  60. Huntly, B. J., Shigematsu, H., Deguchi, K., Lee, B. H., Mizuno, S., Duclos, N., Rowan, R., Amaral, S., Curley, D., Williams, I. R., Akashi, K. and Gilliland, D. G. 2004. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6:587–96.PubMedCrossRefGoogle Scholar
  61. Iscove, N. 1990. Haematopoiesis. Searching for stem cells. Nature 347:126–7.PubMedCrossRefGoogle Scholar
  62. Jamieson, C. H., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., Sawyers, C. L. and Weissman, I. L. 2004. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351:657–67.PubMedCrossRefGoogle Scholar
  63. Jordan, C. T., Upchurch, D., Szilvassy, S. J., Guzman, M. L., Howard, D. S., Pettigrew, A. L., Meyerrose, T., Rossi, R., Grimes, B., Rizzieri, D. A., Luger, S. M. and Phillips, G. L. 2000. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14:1777–84.PubMedCrossRefGoogle Scholar
  64. Jorgensen, H. G., Allan, E. K., Jordanides, N. E., Mountford, J. C. and Holyoake, T. L. 2007. Nilotinib exerts equipotent anti-proliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 109:4016–9.PubMedCrossRefGoogle Scholar
  65. Kaeda, J., Chase, A. and Goldman, J. M. 2002. Cytogenetic and molecular monitoring of residual disease in chronic myeloid leukaemia. Acta Haematol 107:64–75.PubMedCrossRefGoogle Scholar
  66. Kantarjian, H. M., Talpaz, M., Keating, M. J., Estey, E. H., O'Brien, S., Beran, M., McCredie, K. B., Gutterman, J. and Freireich, E. J. 1991. Intensive chemotherapy induction followed by interferon-alpha maintenance in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer 68:1201–7.PubMedCrossRefGoogle Scholar
  67. Kantarjian, H., Giles, F., Wunderle, L., Bhalla, K., O'Brien, S., Wassmann, B., Tanaka, C., Manley, P., Rae, P., Mietlowski, W., Bochinski, K., Hochhaus, A., Griffin, J. D., Hoelzer, D., Albitar, M., Dugan, M., Cortes, J., Alland, L. and Ottmann, O. G. 2006. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542–51.PubMedCrossRefGoogle Scholar
  68. Kantarjian, H. M., O'Brien, S., Huang, X., Garcia-Manero, G., Ravandi, F., Cortes, J., Shan, J., Davisson, J., Bueso-Ramos, C. E. and Issa, J. P. 2007. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience. Cancer 109:1133–7.PubMedCrossRefGoogle Scholar
  69. Kavalerchik, E., Gotlib, J., Geron, I., Abrahamsson, A., Wrasidlo, W., Goff, D., Lu, D., Molinsli, T., Giles, F., Weissman, I., Carson, D. and Jamieson, C. 2006. Inhibition of chronic myelogenous leukemia stem cells with novel WNT antagonists. Blood 108:74a.Google Scholar
  70. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Yilmaz, O. H., Terhorst, C. and Morrison, S. J. 2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121:1109–21.PubMedCrossRefGoogle Scholar
  71. Klein, U., Tu, Y., Stolovitzky, G. A., Mattioli, M., Cattoretti, G., Husson, H., Freedman, A., Inghirami, G., Cro, L., Baldini, L., Neri, A., Califano, A. and Dalla-Favera, R. 2001. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194:1625–38.PubMedCrossRefGoogle Scholar
  72. Kordes, U., Krappmann, D., Heissmeyer, V., Ludwig, W. D. and Scheidereit, C. 2000. Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 14:399–402.PubMedCrossRefGoogle Scholar
  73. Krivtsov, A. V. and Armstrong, S. A. 2007. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7:823–33.PubMedCrossRefGoogle Scholar
  74. Lajtha, L. G. 1979. Stem cell concepts. Differentiation 14:23–34.PubMedCrossRefGoogle Scholar
  75. Leary, A. G., Hirai, Y., Kishimoto, T., Clark, S. C. and Ogawa, M. 1989. Survival of hemopoietic progenitors in the G0 period of the cell cycle does not require early hemopoietic regulators. Proc Natl Acad Sci USA 86:4535–8.PubMedCrossRefGoogle Scholar
  76. Leary, A. G., Zeng, H. Q., Clark, S. C. and Ogawa, M. 1992. Growth factor requirements for survival in G0 and entry into the cell cycle of primitive human hemopoietic progenitors. Proc Natl Acad Sci USA 89:4013–7.PubMedCrossRefGoogle Scholar
  77. Lessard, J. and Sauvageau, G. 2003. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423:255–60.PubMedCrossRefGoogle Scholar
  78. Lugo, T. G., Pendergast, A. M., Muller, A. J. and Witte, O. N. 1990. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247:1079–82.PubMedCrossRefGoogle Scholar
  79. Martin, P. J., Najfeld, V., Hansen, J. A., Penfold, G. K., Jacobson, R. J. and Fialkow, P. J. 1980. Involvement of the B-lymphoid system in chronic myelogenous leukaemia. Nature 287:49–50.PubMedCrossRefGoogle Scholar
  80. Mauro, M. J., Druker, B. J. and Maziarz, R. T. 2004. Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res 28 Suppl 1:S71–3.Google Scholar
  81. Mazieres, J., You, L., He, B., Xu, Z., Lee, A. Y., Mikami, I., McCormick, F. and Jablons, D. M. 2005. Inhibition of Wnt16 in human acute lymphoblastoid leukemia cells containing the t(1;19) translocation induces apoptosis. Oncogene 24:5396–400.PubMedCrossRefGoogle Scholar
  82. McCormack, E., Bruserud, O. and Gjertsen, B. T. 2008. Review: genetic models of acute myeloid leukaemia. Oncogene 27:3765–79.Google Scholar
  83. Merchant, A. A., Joseph, G. A., Jones, E., Lin, T., Smith, B. D., McDevitt, M., Karp, J. E., Peacock, C., Watkins, D. N. and Matsui, W. H. 2007. Hedgehog signaling in normal and malignant hematopoiesis. Blood 110:991a.Google Scholar
  84. Messmer, B. T., Messmer, D., Allen, S. L., Kolitz, J. E., Kudalkar, P., Cesar, D., Murphy, E. J., Koduru, P., Ferrarini, M., Zupo, S., Cutrona, G., Damle, R. N., Wasil, T., Rai, K. R., Hellerstein, M. K. and Chiorazzi, N. 2005. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 115:755–64.PubMedGoogle Scholar
  85. Michor, F., Hughes, T. P., Iwasa, Y., Branford, S., Shah, N. P., Sawyers, C. L. and Nowak, M. A. 2005. Dynamics of chronic myeloid leukaemia. Nature 435:1267–70.PubMedCrossRefGoogle Scholar
  86. Miller, J. S., McCullar, V., Punzel, M., Lemischka, I. R. and Moore, K. A. 1999. Single adult human CD34(+)/Lin-/CD38(-) progenitors give rise to natural killer cells, B-lineage cells, dendritic cells, and myeloid cells. Blood 93:96–106.PubMedGoogle Scholar
  87. Miller, W. H., Jr., Schipper, H. M., Lee, J. S., Singer, J. and Waxman, S. 2002. Mechanisms of action of arsenic trioxide. Cancer Res 62:3893–903.PubMedGoogle Scholar
  88. Morrison, S. J., Wandycz, A. M., Hemmati, H. D., Wright, D. E. and Weissman, I. L. 1997. Identification of a lineage of multipotent hematopoietic progenitors. Development 124:1929–39.PubMedGoogle Scholar
  89. Muller-Tidow, C., Steffen, B., Cauvet, T., Tickenbrock, L., Ji, P., Diederichs, S., Sargin, B., Kohler, G., Stelljes, M., Puccetti, E., Ruthardt, M., deVos, S., Hiebert, S. W., Koeffler, H. P., Berdel, W. E. and Serve, H. 2004. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol Cell Biol 24:2890–904.PubMedCrossRefGoogle Scholar
  90. Nakagawa, R., Soh, J. W. and Michie, A. M. 2006. Subversion of protein kinase C alpha signaling in hematopoietic progenitor cells results in the generation of a B-cell chronic lymphocytic leukemia-like population in vivo. Cancer Res 66:527–34.PubMedCrossRefGoogle Scholar
  91. O'Brien, S. G., Guilhot, F., Larson, R. A., Gathmann, I., Baccarani, M., Cervantes, F., Cornelissen, J. J., Fischer, T., Hochhaus, A., Hughes, T., Lechner, K., Nielsen, J. L., Rousselot, P., Reiffers, J., Saglio, G., Shepherd, J., Simonsson, B., Gratwohl, A., Goldman, J. M., Kantarjian, H., Taylor, K., Verhoef, G., Bolton, A. E., Capdeville, R. and Druker, B. J. 2003. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004.PubMedCrossRefGoogle Scholar
  92. O'Hare, T., Walters, D. K., Stoffregen, E. P., Jia, T., Manley, P. W., Mestan, J., Cowan-Jacob, S. W., Lee, F. Y., Heinrich, M. C., Deininger, M. W. and Druker, B. J. 2005. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65:4500–5.PubMedCrossRefGoogle Scholar
  93. Oki, Y., Kantarjian, H. M., Gharibyan, V., Jones, D., O'Brien, S., Verstovsek, S., Cortes, J., Morris, G. M., Garcia-Manero, G. and Issa, J. P. 2007. Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer 109:899–906.PubMedCrossRefGoogle Scholar
  94. Passegue, E., Jamieson, C. H., Ailles, L. E. and Weissman, I. L. 2003. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci USA 100 Suppl 1:11842–9.CrossRefGoogle Scholar
  95. Petropoulos, K., Arseni, N., Schessl, C., Stadler, C. R., Rawat, V. P., Deshpande, A. J., Heilmeier, B., Hiddemann, W., Quintanilla-Martinez, L., Bohlander, S. K., Feuring-Buske, M. and Buske, C. 2008. A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Med 205:515–22.PubMedCrossRefGoogle Scholar
  96. Pettengell, R., Luft, T., Henschler, R., Hows, J. M., Dexter, T. M., Ryder, D. and Testa, N. G. 1994. Direct comparison by limiting dilution analysis of long-term culture-initiating cells in human bone marrow, umbilical cord blood, and blood stem cells. Blood 84:3653–9.PubMedGoogle Scholar
  97. Pineault, N., Helgason, C. D., Lawrence, H. J. and Humphries, R. K. 2002. Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol 30:49–57.PubMedCrossRefGoogle Scholar
  98. Plimack, E. R., Kantarjian, H. M. and Issa, J. P. 2007. Decitabine and its role in the treatment of hematopoietic malignancies. Leuk Lymphoma 48:1472–81.PubMedCrossRefGoogle Scholar
  99. Radich, J. P., Dai, H., Mao, M., Oehler, V., Schelter, J., Druker, B., Sawyers, C., Shah, N., Stock, W., Willman, C. L., Friend, S. and Linsley, P. S. 2006. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 103:2794–9.PubMedCrossRefGoogle Scholar
  100. Raza-Egilmez, S. Z., Jani-Sait, S. N., Grossi, M., Higgins, M. J., Shows, T. B. and Aplan, P. D. 1998. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia. Cancer Res 58:4269–73.PubMedGoogle Scholar
  101. Roeder, I., Horn, M., Glauche, I., Hochhaus, A., Mueller, M. C. and Loeffler, M. 2006. Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med 12:1181–4.PubMedCrossRefGoogle Scholar
  102. Rowley, J. D. 1973. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290–3.PubMedCrossRefGoogle Scholar
  103. Shah, N. P., Nicoll, J. M., Nagar, B., Gorre, M. E., Paquette, R. L., Kuriyan, J. and Sawyers, C. L. 2002. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117–25.PubMedCrossRefGoogle Scholar
  104. Shah, N. P., Tran, C., Lee, F. Y., Chen, P., Norris, D. and Sawyers, C. L. 2004. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399–401.PubMedCrossRefGoogle Scholar
  105. Sieburg, H. B., Cho, R. H. and Muller-Sieburg, C. E. 2002. Limiting dilution analysis for estimating the frequency of hematopoietic stem cells: uncertainty and significance. Exp Hematol 30:1436–43.PubMedCrossRefGoogle Scholar
  106. Siminovitch, L., McCulloch, E. A. and Till, J. E. 1963. The distribution of colony-forming cells among spleen colonies. J Cell Physiol 62:327–36.PubMedCrossRefGoogle Scholar
  107. Simmons, P. J., Levesque, J. P. and Haylock, D. N. 2001. Mucin-like molecules as modulators of the survival and proliferation of primitive hematopoietic cells. Ann N Y Acad Sci 938:196–206; discussion 206–7.PubMedCrossRefGoogle Scholar
  108. Simon, M., Grandage, V. L., Linch, D. C. and Khwaja, A. 2005. Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia. Oncogene 24:2410–20.PubMedCrossRefGoogle Scholar
  109. Spangrude, G. J., Heimfeld, S. and Weissman, I. L. 1988. Purification and characterization of mouse hematopoietic stem cells. Science 241:58–62.PubMedCrossRefGoogle Scholar
  110. Stevenson, F. K. and Caligaris-Cappio, F. 2004. Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood 103:4389–95.PubMedCrossRefGoogle Scholar
  111. Strauss, A. C., Chu, S., Holyoake, T. and Bhatia, R. 2007. Effective induction of apoptosis in chronic myeloid leukemia CD34+ cells by histone deacetylase inhibitor LAQ824 in combination with imatinib. Blood 110:312a.Google Scholar
  112. Sutherland, H. J., Eaves, C. J., Lansdorp, P. M., Thacker, J. D. and Hogge, D. E. 1991. Differential regulation of primitive human hematopoietic cells in long-term cultures maintained on genetically engineered murine stromal cells. Blood 78:666–72.PubMedGoogle Scholar
  113. Talpaz, M., Shah, N. P., Kantarjian, H., Donato, N., Nicoll, J., Paquette, R., Cortes, J., O'Brien, S., Nicaise, C., Bleickardt, E., Blackwood-Chirchir, M. A., Iyer, V., Chen, T. T., Huang, F., Decillis, A. P. and Sawyers, C. L. 2006. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531–41.PubMedCrossRefGoogle Scholar
  114. Terpstra, W., Ploemacher, R. E., Prins, A., van Lom, K., Pouwels, K., Wognum, A. W., Wagemaker, G., Lowenberg, B. and Wielenga, J. J. 1996. Fluorouracil selectively spares acute myeloid leukemia cells with long-term growth abilities in immunodeficient mice and in culture. Blood 88:1944–50.PubMedGoogle Scholar
  115. Till, J. E. and McCulloch, E. A. 1961. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–22.PubMedCrossRefGoogle Scholar
  116. Vickers, M., Brown, G. C., Cologne, J. B. and Kyoizumi, S. 2000. Modelling haemopoietic stem cell division by analysis of mutant red cells. Br J Haematol 110:54–62.PubMedCrossRefGoogle Scholar
  117. Vonderheide, R. H., Domchek, S. M., Schultze, J. L., George, D. J., Hoar, K. M., Chen, D. Y., Stephans, K. F., Masutomi, K., Loda, M., Xia, Z., Anderson, K. S., Hahn, W. C. and Nadler, L. M. 2004. Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes. Clin Cancer Res 10:828–39.PubMedCrossRefGoogle Scholar
  118. Wang, J. C., Doedens, M. and Dick, J. E. 1997. Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay. Blood 89:3919–24.PubMedGoogle Scholar
  119. Wang, J. C., Lapidot, T., Cashman, J. D., Doedens, M., Addy, L., Sutherland, D. R., Nayar, R., Laraya, P., Minden, M., Keating, A., Eaves, A. C., Eaves, C. J. and Dick, J. E. 1998. High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 91:2406–14.PubMedGoogle Scholar
  120. Weissman, I. L. 2000. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287:1442–6.PubMedCrossRefGoogle Scholar
  121. Wilson, A. and Trumpp, A. 2006. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6:93–106.PubMedCrossRefGoogle Scholar
  122. Wong, S. and Witte, O. N. 2004. The BCR-ABL story: bench to bedside and back. Annu Rev Immunol 22:247–306.PubMedCrossRefGoogle Scholar
  123. Yilmaz, O. H., Valdez, R., Theisen, B. K., Guo, W., Ferguson, D. O., Wu, H. and Morrison, S. J. 2006. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441:475–82.PubMedCrossRefGoogle Scholar
  124. Zhao, C., Blum, J., Chen, A., Kwon, H. Y., Jung, S. H., Cook, J. M., Lagoo, A. and Reya, T. 2007. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12:528–41.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Mhairi Copland
    • 1
  • Alison M. Michie
    • 2
  • Tessa L. Holyoake
    • 2
  1. 1.University of GlasgowGlasgowUK
  2. 2.Section of Experimental HematologyUniversity of GlasgowGlasgowUK

Personalised recommendations