Protein & Cell

, Volume 4, Issue 3, pp 186–196 | Cite as

Molecular mechanisms for survival regulation of chronic myeloid leukemia stem cells



Studies on chronic myeloid leukemia (CML) have served as a paradigm for cancer research and therapy. These studies involve the identification of the first cancer-associated chromosomal abnormality and the subsequent development of tyrosine kinase inhibitors (TKIs) that inhibit BCR-ABL kinase activity in CML. It becomes clear that leukemia stem cells (LSCs) in CML which are resistant to TKIs, and eradication of LSCs appears to be extremely difficult. Therefore, one of the major issues in current CML biology is to understand the biology of LSCs and to investigate why LSCs are insensitive to TKI monotherapy for developing curative therapeutic strategies. Studies from our group and others have revealed that CML LSCs form a hierarchy similar to that seen in normal hematopoiesis, in which a rare stem cell population with limitless self-renewal potential gives rise to progenies that lack such potential. LSCs also possess biological features that are different from those of normal hematopoietic stem cells (HSCs) and are critical for their malignant characteristics. In this review, we summarize the latest progress in CML field, and attempt to understand the molecular mechanisms of survival regulation of LSCs.


molecular mechanisms chronic myeloid leukemia leukemia stem cell 


  1. Adrian, F.J., Ding, Q., Sim, T., Velentza, A., Sloan, C., Liu, Y., Zhang, G., Hur, W., Ding, S., Manley, P., et al. (2006). Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol 2, 95–102.CrossRefGoogle Scholar
  2. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., and Clarke, M.F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100, 3983–3988.CrossRefGoogle Scholar
  3. Bhatia, R., Holtz, M., Niu, N., Gray, R., Snyder, D.S., Sawyers, C.L., Arber, D.A., Slovak, M.L., and Forman, S.J. (2003). Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101, 4701–4707.CrossRefGoogle Scholar
  4. 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, 730–737.CrossRefGoogle Scholar
  5. Chan, W.W., Wise, S.C., Kaufman, M.D., Ahn, Y.M., Ensinger, C.L., Haack, T., Hood, M.M., Jones, J., Lord, J.W., Lu, W.P., et al. (2011). Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell 19, 556–568.CrossRefGoogle Scholar
  6. Chen, Y., Hu, Y., Zhang, H., Peng, C., and Li, S. (2009). Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet 41, 783–792.CrossRefGoogle Scholar
  7. Chen, Y., Peng, C., Li, D., and Li, S. (2010a). Molecular and cellular bases of chronic myeloid leukemia. Protein Cell 1, 124–132.CrossRefGoogle Scholar
  8. Chen, Y., Peng, C., Sullivan, C., Li, D., and Li, S. (2010b). Critical molecular pathways in cancer stem cells of chronic myeloid leukemia. Leukemia 24, 1545–1554.CrossRefGoogle Scholar
  9. Corbin, A.S., Agarwal, A., Loriaux, M., Cortes, J., Deininger, M.W., and Druker, B.J. (2011). Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 121, 396–409.CrossRefGoogle Scholar
  10. Cortes, J., O’Brien, S., and Kantarjian, H. (2004). Discontinuation of imatinib therapy after achieving a molecular response. Blood 104, 2204–2205.CrossRefGoogle Scholar
  11. Cortes, J., Rousselot, P., Kim, D.W., Ritchie, E., Hamerschlak, N., Coutre, S., Hochhaus, A., Guilhot, F., Saglio, G., Apperley, J., et al. (2007). Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109, 3207–3213.CrossRefGoogle Scholar
  12. Dang, L., White, D.W., Gross, S., Bennett, B.D., Bittinger, M.A., Driggers, E.M., Fantin, V.R., Jang, H.G., Jin, S., Keenan, M.C., et al. (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744.CrossRefGoogle Scholar
  13. Dierks, C., Beigi, R., Guo, G.R., Zirlik, K., Stegert, M.R., Manley, P., Trussell, C., Schmitt-Graeff, A., Landwerlin, K., Veelken, H., et al. (2008). Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14, 238–249.CrossRefGoogle Scholar
  14. Donato, N.J., Wu, J.Y., Stapley, J., Gallick, G., Lin, H., Arlinghaus, R., and Talpaz, M. (2003). BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101, 690–698.CrossRefGoogle Scholar
  15. 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., et al. (2006). Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355, 2408–2417.CrossRefGoogle Scholar
  16. Druker, B.J., Sawyers, C.L., Kantarjian, H., Resta, D.J., Reese, S.F., Ford, J.M., Capdeville, R., and Talpaz, M. (2001a). Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344, 1038–1042.CrossRefGoogle Scholar
  17. 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., et al. (2001b). Efficacy and safety of a specific inhibitor of the BCRABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344, 1031–1037.CrossRefGoogle Scholar
  18. 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, 561–566.CrossRefGoogle Scholar
  19. Duy, C., Hurtz, C., Shojaee, S., Cerchietti, L., Geng, H., Swaminathan, S., Klemm, L., Kweon, S.M., Nahar, R., Braig, M., et al. (2011). BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature 473, 384–388.CrossRefGoogle Scholar
  20. Duy, C., Yu, J.J., Nahar, R., Swaminathan, S., Kweon, S.M., Polo, J.M., Valls, E., Klemm, L., Shojaee, S., Cerchietti, L., et al. (2010). BCL6 is critical for the development of a diverse primary B cell repertoire. J Exp Med 207, 1209–1221.CrossRefGoogle Scholar
  21. Falvella, F.S., Pascale, R.M., Gariboldi, M., Manenti, G., De Miglio, M.R., Simile, M.M., Dragani, T.A., and Feo, F. (2002). Stearoyl-CoA desaturase 1 (Scd1) gene overexpression is associated with genetic predisposition to hepatocarcinogenesis in mice and rats. Carcinogenesis 23, 1933–1936.CrossRefGoogle Scholar
  22. Flowers, J.B., Rabaglia, M.E., Schueler, K.L., Flowers, M.T., Lan, H., Keller, M.P., Ntambi, J.M., and Attie, A.D. (2007). Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice. Diabetes 56, 1228–1239.CrossRefGoogle Scholar
  23. Frank, D.A., and Varticovski, L. (1996). BCR/abl leads to the constitutive activation of Stat proteins, and shares an epitope with tyrosine phosphorylated Stats. Leukemia 10, 1724–1730.Google Scholar
  24. Goldstein, A.S., Huang, J., Guo, C., Garraway, I.P., and Witte, O.N. (2010). Identification of a cell of origin for human prostate cancer. Science 329, 568–571.CrossRefGoogle Scholar
  25. Gorre, M.E., Ellwood-Yen, K., Chiosis, G., Rosen, N., and Sawyers, C.L. (2002). BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood 100, 3041–3044.CrossRefGoogle Scholar
  26. 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, 876–880.CrossRefGoogle Scholar
  27. 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, 319–325.CrossRefGoogle Scholar
  28. Guilhot, F., Apperley, J., Kim, D.W., Bullorsky, E.O., Baccarani, M., Roboz, G.J., Amadori, S., de Souza, C.A., Lipton, J.H., Hochhaus, A., et al. (2007). Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109, 4143–4150.CrossRefGoogle Scholar
  29. Hamilton, A., Helgason, G., Schemionek, M., Zhang, B., Myssina, S., Allan, E.K., Nicolini, F.E., Müller-Tidow, C., Bhatia, R., Brunton, V.G., et al. (2012). Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood 119, 1501–1510.CrossRefGoogle Scholar
  30. Harder, K.W., Parsons, L.M., Armes, J., Evans, N., Kountouri, N., Clark, R., Quilici, C., Grail, D., Hodgson, G.S., Dunn, A.R., et al. (2001). Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. Immunity 15, 603–615.CrossRefGoogle Scholar
  31. Hess, D., Chisholm, J.W., and Igal, R.A. (2010). Inhibition of stearoyl-CoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells. PLoS One 5, e11394.CrossRefGoogle Scholar
  32. Hochhaus, A., Kantarjian, H.M., Baccarani, M., Lipton, J.H., Apperley, J.F., Druker, B.J., Facon, T., Goldberg, S.L., Cervantes, F., Niederwieser, D., et al. (2007). Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109, 2303–2309.CrossRefGoogle Scholar
  33. Hu, Y., Liu, Y., Pelletier, S., Buchdunger, E., Warmuth, M., Fabbro, D., Hallek, M., Van Etten, R.A., and Li, S. (2004). Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 36, 453–461.CrossRefGoogle Scholar
  34. Hu, Y., Swerdlow, S., Duffy, T.M., Weinmann, R., Lee, F.Y., and Li, S. (2006). Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci U S A 103, 16870–16875.CrossRefGoogle Scholar
  35. Huntly, B.J., and Gilliland, D.G. (2005). Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 5, 311–321.CrossRefGoogle Scholar
  36. Huntly, B.J., Shigematsu, H., Deguchi, K., Lee, B.H., Mizuno, S., Duclos, N., Rowan, R., Amaral, S., Curley, D., Williams, I.R., et al. (2004). MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596.CrossRefGoogle Scholar
  37. Hurtz, C., Hatzi, K., Cerchietti, L., Braig, M., Park, E., Kim, Y.M., Herzog, S., Ramezani-Rad, P., Jumaa, H., Muller, M.C., et al. (2011). BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med 208, 2163–2174.CrossRefGoogle Scholar
  38. Ito, K., Carracedo, A., Weiss, D., Arai, F., Ala, U., Avigan, D.E., Schafer, Z.T., Evans, R.M., Suda, T., Lee, C.H., et al. (2012). A PML-PPARdelta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med 18, 1350–1358.CrossRefGoogle Scholar
  39. Kantarjian, H., Giles, F., Wunderle, L., Bhalla, K., O’Brien, S., Wassmann, B., Tanaka, C., Manley, P., Rae, P., Mietlowski, W., et al. (2006). Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354, 2542–2551.CrossRefGoogle Scholar
  40. Keith, B., and Simon, M.C. (2007). Hypoxia-inducible factors, stem cells, and cancer. Cell 129, 465–472.CrossRefGoogle Scholar
  41. Kim, C.F., Jackson, E.L., Woolfenden, A.E., Lawrence, S., Babar, I., Vogel, S., Crowley, D., Bronson, R.T., and Jacks, T. (2005). Identi-fication of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835.CrossRefGoogle Scholar
  42. Kim, Y.C., and Ntambi, J.M. (1999). Regulation of stearoyl-CoA de saturase genes: role in cellular metabolism and preadipocyte differentiation. Biochem Biophys Res Commun 266, 1–4.CrossRefGoogle Scholar
  43. Kinder, M., Wei, C., Shelat, S.G., Kundu, M., Zhao, L., Blair, I.A., and Pure, E. (2010). Hematopoietic stem cell function requires 12/15-lipoxygenase-dependent fatty acid metabolism. Blood 115, 5012–5022.CrossRefGoogle Scholar
  44. Konig, H., Copland, M., Chu, S., Jove, R., Holyoake, T.L., and Bhatia, R. (2008). Effects of dasatinib on SRC kinase activity and downstream intracellular signaling in primitive chronic myelogenous leukemia hematopoietic cells. Cancer Res 68, 9624–9633.CrossRefGoogle Scholar
  45. Lessard, J., and Sauvageau, G. (2003). Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260.CrossRefGoogle Scholar
  46. Li, C., Heidt, D.G., Dalerba, P., Burant, C.F., Zhang, L., Adsay, V., Wicha, M., Clarke, M.F., and Simeone, D.M. (2007). Identification of pancreatic cancer stem cells. Cancer Res 67, 1030–1037.CrossRefGoogle Scholar
  47. Lombardo, L.J., Lee, F.Y., Chen, P., Norris, D., Barrish, J.C., Behnia, K., Castaneda, S., Cornelius, L.A., Das, J., Doweyko, A.M., et al. (2004). Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47, 6658–6661.CrossRefGoogle Scholar
  48. Mayerhofer, M., Valent, P., Sperr, W.R., Griffin, J.D., and Sillaber, C. (2002). BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 100, 3767–3775.CrossRefGoogle Scholar
  49. Melo, J.V., and Barnes, D.J. (2007). Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 7, 441–453.CrossRefGoogle Scholar
  50. Mendez, O., Zavadil, J., Esencay, M., Lukyanov, Y., Santovasi, D., Wang, S.C., Newcomb, E.W., and Zagzag, D. (2010). Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9, 133.CrossRefGoogle Scholar
  51. Meng, F., and Lowell, C.A. (1997). Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn. J Exp Med 185, 1661–1670.CrossRefGoogle Scholar
  52. Naka, K., Hoshii, T., Muraguchi, T., Tadokoro, Y., Ooshio, T., Kondo, Y., Nakao, S., Motoyama, N., and Hirao, A. (2010). TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676–680.CrossRefGoogle Scholar
  53. Neshat, M.S., Raitano, A.B., Wang, H.G., Reed, J.C., and Sawyers, C.L. (2000). The survival function of the Bcr-Abl oncogene is mediated by Bad-dependent and -independent pathways: roles for phosphatidylinositol 3-kinase and Raf. Mol Cell Biol 20, 1179–1186.CrossRefGoogle Scholar
  54. Nowell P.C., and Hungerford, H.D. (1960). A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497.Google Scholar
  55. Ntambi, J.M., and Miyazaki, M. (2003). Recent insights into stearoyl-CoA desaturase-1. Curr Opin Lipidol 14, 255–261.CrossRefGoogle Scholar
  56. O’Hare, T., Eide, C.A., and Deininger, M.W. (2007). Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110, 2242–2249.CrossRefGoogle Scholar
  57. Ottmann, O., Dombret, H., Martinelli, G., Simonsson, B., Guilhot, F., Larson, R.A., Rege-Cambrin, G., Radich, J., Hochhaus, A., Apanovitch, A.M., et al. (2007). Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 110, 2309–2315.CrossRefGoogle Scholar
  58. Park, I.K., Qian, D., Kiel, M., Becker, M.W., Pihalja, M., Weissman, I.L., Morrison, S.J., and Clarke, M.F. (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305.CrossRefGoogle Scholar
  59. Peng, C., Chen, Y., Yang, Z., Zhang, H., Osterby, L., Rosmarin, A.G., and Li, S. (2010). PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice. Blood 115, 626–635.CrossRefGoogle Scholar
  60. Phan, R.T., and Dalla-Favera, R. (2004). The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635–639.CrossRefGoogle Scholar
  61. Piazza, R.G., Magistroni, V., Andreoni, F., Franceschino, A., Tornaghi, L., Varella-Garcia, M., Bungaro, S., Colnaghi, F., Corneo, G., Pogliani, E.M., et al. (2005). Imatinib dose increase up to 1200 mg daily can induce new durable complete cytogenetic remissions in relapsed Ph+ chronic myeloid leukemia patients. Leukemia 19, 1985–1987.CrossRefGoogle Scholar
  62. Puil, L., Liu, J., Gish, G., Mbamalu, G., Bowtell, D., Pelicci, P.G., Arlinghaus, R., and Pawson, T. (1994). Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J 13, 764–773.Google Scholar
  63. Quintas-Cardama, A., Kantarjian, H., and Cortes, J. (2007). Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov 6, 834–848.CrossRefGoogle Scholar
  64. Rahman, S.M., Dobrzyn, A., Dobrzyn, P., Lee, S.H., Miyazaki, M., and Ntambi, J.M. (2003). Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates proteintyrosine phosphatase 1B in muscle. Proc Natl Acad Sci U S A 100, 11110–11115.CrossRefGoogle Scholar
  65. Ren, R. (2005). Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5, 172–183.CrossRefGoogle Scholar
  66. Reya, T., Morrison, S.J., Clarke, M.F., and Weissman, I.L. (2001). Stem cells, cancer, and cancer stem cells. Nature 414, 105–111.CrossRefGoogle Scholar
  67. Reynaud, D., Pietras, E., Barry-Holson, K., Mir, A., Binnewies, M., Jeanne, M., Sala-Torra, O., Radich, J.P., and Passegue, E. (2011). IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell 20, 661–673.CrossRefGoogle Scholar
  68. Ricci-Vitiani, L., Lombardi, D.G., Pilozzi, E., Biffoni, M., Todaro, M., Peschle, C., and De Maria, R. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115.CrossRefGoogle Scholar
  69. Saijo, K., Schmedt, C., Su, I.H., Karasuyama, H., Lowell, C.A., Reth, M., Adachi, T., Patke, A., Santana, A., and Tarakhovsky, A. (2003). Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development. Nat Immunol 4, 274–279.CrossRefGoogle Scholar
  70. Sampath, H., and Ntambi, J.M. (2011). The role of stearoyl-CoA desaturase in obesity, insulin resistance, and inflammation. Ann N Y Acad Sci 1243, 47–53.CrossRefGoogle Scholar
  71. Savona, M., and Talpaz, M. (2008). Getting to the stem of chronic myeloid leukaemia. Nat Rev Cancer 8, 341–350.CrossRefGoogle Scholar
  72. Scaglia, N., Chisholm, J.W., and Igal, R.A. (2009). Inhibition of stearoylCoA desaturase-1 inactivates acetyl-CoA carboxylase and impairs proliferation in cancer cells: role of AMPK. PLoS One 4, e 6812.CrossRefGoogle Scholar
  73. Scaglia, N., and Igal, R.A. (2005). Stearoyl-CoA desaturase is involved in the control of proliferation, anchorage-independent growth, and survival in human transformed cells. J Biol Chem 280, 25339–25349.CrossRefGoogle Scholar
  74. Schindler, T., Bornmann, W., Pellicena, P., Miller, W.T., Clarkson, B., and Kuriyan, J. (2000). Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289, 1938–1942.CrossRefGoogle Scholar
  75. Semenza, G.L. (2003). Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721–732.CrossRefGoogle Scholar
  76. 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.CrossRefGoogle Scholar
  77. Simon, M.C., and Keith, B. (2008). The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9, 285–296.CrossRefGoogle Scholar
  78. Singh, S.K., Clarke, I.D., Terasaki, M., Bonn, V.E., Hawkins, C., Squire, J., and Dirks, P.B. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res 63, 5821–5828.Google Scholar
  79. Soeda, A., Park, M., Lee, D., Mintz, A., Androutsellis-Theotokis, A., McKay, R.D., Engh, J., Iwama, T., Kunisada, T., Kassam, A.B., et al. (2009). Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28, 3949–3959.CrossRefGoogle Scholar
  80. Talpaz, M., Shah, N.P., Kantarjian, H., Donato, N., Nicoll, J., Paquette, R., Cortes, J., O’Brien, S., Nicaise, C., Bleickardt, E., et al. (2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354, 2531–2541.CrossRefGoogle Scholar
  81. Texido, G., Su, I.H., Mecklenbrauker, I., Saijo, K., Malek, S.N., Desiderio, S., Rajewsky, K., and Tarakhovsky, A. (2000). The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation. Mol Cell Biol 20, 1227–1233.CrossRefGoogle Scholar
  82. Visvader, J.E., and Lindeman, G.J. (2008). Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8, 755–768.CrossRefGoogle Scholar
  83. Wang, J.C., and Dick, J.E. (2005). Cancer stem cells: lessons from leukemia. Trends Cell Biol 15, 494–501.CrossRefGoogle Scholar
  84. Wang, Y., Liu, Y., Malek, S.N., Zheng, P., and Liu, Y. (2011). Targeting HIF1a eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 8, 399–411.CrossRefGoogle Scholar
  85. Ward, P.S., Patel, J., Wise, D.R., Abdel-Wahab, O., Bennett, B.D., Coller, H.A., Cross, J.R., Fantin, V.R., Hedvat, C.V., Perl, A.E., et al. (2010). The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alphaketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234.CrossRefGoogle Scholar
  86. Warmuth, M., Bergmann, M., Priess, A., Hauslmann, K., Emmerich, B., and Hallek, M. (1997). The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr. J Biol Chem 272, 33260–33270.CrossRefGoogle Scholar
  87. Weisberg, E., Manley, P.W., Breitenstein, W., Bruggen, J., Cowan-Jacob, S.W., Ray, A., Huntly, B., Fabbro, D., Fendrich, G., Hall-Meyers, E., et al. (2005). Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7, 129–141.CrossRefGoogle Scholar
  88. Wong, S., and Witte, O.N. (2004). The BCR-ABL story: bench to bedside and back. Annu Rev Immunol 22, 247–306.CrossRefGoogle Scholar
  89. Wu, J., Meng, F., Lu, H., Kong, L., Bornmann, W., Peng, Z., Talpaz, M., and Donato, N.J. (2008). Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood 111, 3821–3829.CrossRefGoogle Scholar
  90. Xiao, W., Hong, H., Kawakami, Y., Lowell, C.A., and Kawakami, T. (2008). Regulation of myeloproliferation and M2 macrophage programming in mice by Lyn/Hck, SHIP, and Stat5. J Clin Invest 118, 924–934.Google Scholar
  91. Zhang, H., Li, H., Ho, N., Li, D., and Li, S. (2012a). Scd1 plays a tumorsuppressive role in survival of leukemia stem cells and the development of chronic myeloid leukemia. Mol Cell Biol 32, 1776–1787.CrossRefGoogle Scholar
  92. Zhang, H., Li, H., Xi, H.S., and Li, S. (2012b). HIF1alpha is required for survival maintenance of chronic myeloid leukemia stem cells. Blood 119, 2595–2607.CrossRefGoogle Scholar
  93. Zhang, H., Peng, C., Hu, Y., Li, H., Sheng, Z., Chen, Y., Sullivan, C., Cerny, J., Hutchinson, L., Higgins, A., et al. (2012c). The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nat Genet 44, 861–871.CrossRefGoogle Scholar
  94. Zhang, J., Adrian, F.J., Jahnke, W., Cowan-Jacob, S.W., Li, A.G., Iacob, R.E., Sim, T., Powers, J., Dierks, C., Sun, F., et al. (2011). Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463, 501–506.CrossRefGoogle Scholar
  95. 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, 528–541.CrossRefGoogle Scholar
  96. Zhao, C., Chen, A., Jamieson, C.H., Fereshteh, M., Abrahamsson, A., Blum, J., Kwon, H.Y., Kim, J., Chute, J.P., Rizzieri, D., et al. (2009). Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779.CrossRefGoogle Scholar
  97. Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M.M., Simons, J.W., and Semenza, G.L. (2000). Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60, 1541–1545.Google Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations