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.

  • Review
  • Published:

Chronic myelogenous leukemia: mechanisms underlying disease progression

Abstract

Chronic myelogenous leukemia (CML), characterized by the BCR-ABL gene rearrangement, has been extensively studied. Significant progress has been made in the area of BCR-ABL-mediated intracellular signaling, which has led to a better understanding of BCR-ABL-mediated clinical features in chronic phase CML. Disease progression and blast crisis CML is associated with characteristic non-random cytogenetic and molecular events. These can be viewed as increased oncogenic activity or loss of tumor suppressor activity. However, what causes transformation and disease progression to blast crisis is only poorly understood. This is in part due to the lack of a good in vivo model of chronic phase CML even though animal models developed over the last few years have started to provide insights into blast crisis development. Thus, additional in vitro and in vivo studies will be needed to provide a complete understanding of the contribution of BCR-ABL and other genes to disease progression and to improve therapeutic approaches for blast crisis CML.

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

Similar content being viewed by others

References

  1. Savage DG, Szydlo RM, Goldman JM . Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period Br J Haematol 1997 96: 111–116

    CAS  PubMed  Google Scholar 

  2. Spiers AS . The clinical features of chronic granulocytic leukaemia Clin Haematol 1977 6: 77–95

    CAS  PubMed  Google Scholar 

  3. Kantarjian HM, Keating MJ, Talpaz M, Walters RS, Smith TL, Cork A, McCredie KB, Freireich EJ . Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients Am J Med 1987 83: 445–454

    CAS  PubMed  Google Scholar 

  4. Kantarjian HM, Talpaz M . Definition of the accelerated phase of chronic myelogenous leukemia (letter) J Clin Oncol 1988 6: 180–182

    CAS  PubMed  Google Scholar 

  5. Passweg JR, Rowlings PA, Horowitz MM . Related donor bone marrow transplantation for chronic myelogenous leukemia Hematol Oncol Clin N Am 1998 12: 81–92

    CAS  Google Scholar 

  6. Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M, Tura S . An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology Blood 1999 94: 1517–1536

    CAS  PubMed  Google Scholar 

  7. McGlave PB, Shu XO, Wen W, Anasetti C, Nademanee A, Champlin R, Antin JH, Kernan NA, King R, Weisdorf DJ . Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years’ experience of the national marrow donor program Blood 2000 95: 2219–2225

    CAS  PubMed  Google Scholar 

  8. Kantarjian HM, Smith TL, O'Brien S, Beran M, Pierce S, Talpaz M . Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service Ann Intern Med 1995 122: 254–261

    CAS  PubMed  Google Scholar 

  9. Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products Science 1990 247: 1079–1082

    CAS  PubMed  Google Scholar 

  10. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome Science 1990 247: 824–830

    Article  CAS  PubMed  Google Scholar 

  11. Elefanty AG, Hariharan IK, Cory S . bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice EMBO J 1990 9: 1069–1078

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J . Acute leukaemia in bcr/abl transgenic mice Nature 1990 344: 251–253

    Article  CAS  PubMed  Google Scholar 

  13. Gishizky ML, Johnson-White J, Witte ON . Efficient transplantation of BCR-ABL-induced chronic myelogenous leukemia-like syndrome in mice Proc Natl Acad Sci USA 1993 90: 3755–3759

    CAS  PubMed  PubMed Central  Google Scholar 

  14. McLaughlin J, Chianese E, Witte ON . In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome Proc Natl Acad Sci USA 1987 84: 6558–6562

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gishizky ML, Witte ON . Initiation of deregulated growth of multipotent progenitor cells by bcr-abl in vitro Science 1992 256: 836–839

    CAS  PubMed  Google Scholar 

  16. Nowell P, Hungerford D . A minute chromosome in human chronic granulocytic leukemia Science 1960 132: 1497

    Google Scholar 

  17. Rowley JD . Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining Nature 1973 243: 290–293

    CAS  PubMed  Google Scholar 

  18. Groffen J, Heisterkamp N . The BCR/ABL hybrid gene Baillières Clin Haematol 1987 1: 983–999

    CAS  PubMed  Google Scholar 

  19. Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products Science 1990 247: 1079–1082

    CAS  PubMed  Google Scholar 

  20. Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D . The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene Science 1986 233: 212–214

    CAS  PubMed  Google Scholar 

  21. McWhirter JR, Wang JY . An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias EMBO J 1993 12: 1533–1546

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Sirard C, Laneuville P, Dick JE . Expression of bcr-abl abrogates factor-dependent growth of human hematopoietic M07E cells by an autocrine mechanism Blood 1994 83: 1575–1585

    CAS  PubMed  Google Scholar 

  23. Honda H, Oda H, Suzuki T, Takahashi T, Witte ON, Ozawa K, Ishikawa T, Yazaki Y, Hirai H . Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl: a novel transgenic model for human Ph1-positive leukemias Blood 1998 91: 2067–2075

    CAS  PubMed  Google Scholar 

  24. Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC, Pendergast AM, Bronson R, Aster JC, Scott ML, Baltimore D . Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow Blood 1998 92: 3780–3792

    CAS  PubMed  Google Scholar 

  25. Kelliher MA, McLaughlin J, Witte ON, Rosenberg N . Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL [published erratum appears in Proc Natl Acad Sci USA 1990 Nov; 87(22):9072] Proc Natl Acad Sci USA 1990 87: 6649–6653

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Voncken JW, Kaartinen V, Pattengale PK, Germeraad WT, Groffen J, Heisterkamp N . BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice Blood 1995 86: 4603–4611

    CAS  PubMed  Google Scholar 

  27. Li S, Ilaria RL Jr, Million RP, Daley GQ, Van Etten RA . The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity J Exp Med 1999 189: 1399–1412

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Laneuville P . Abl tyrosine protein kinase Semin Immunol 1995 7: 255–266

    CAS  PubMed  Google Scholar 

  29. Wang JY . Abl tyrosine kinase in signal transduction and cell-cycle regulation Curr Opin Genet Dev 1993 3: 35–43

    CAS  PubMed  Google Scholar 

  30. Sawyers CL, Callahan W, Witte ON . Dominant negative MYC blocks transformation by ABL oncogenes Cell 1992 70: 901–910

    CAS  PubMed  Google Scholar 

  31. Wickremasinghe RG, Hoffbrand AV . Biochemical and genetic control of apoptosis: relevance to normal hematopoiesis and hematological malignancies Blood 1999 93: 3587–3600

    CAS  PubMed  Google Scholar 

  32. Wen ST, Jackson PK, Van Etten RA . The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products EMBO J 1996 15: 1583–1595

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Agami R, Blandino G, Oren M, Shaul Y . Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis Nature 1999 399: 809–813

    CAS  PubMed  Google Scholar 

  34. Baskaran R, Wood LD, Whitaker LL, Canman CE, Morgan SE, Xu Y, Barlow C, Baltimore D, Wynshaw-Boris A, Kastan MB, Wang JY . Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation Nature 1997 387: 516–519

    CAS  PubMed  Google Scholar 

  35. Kharbanda S, Yuan ZM, Weichselbaum R, Kufe D . Functional role for the c-Abl protein tyrosine kinase in the cellular response to genotoxic stress Biochim Biophys Acta 1997 1333: O1–O7

    CAS  PubMed  Google Scholar 

  36. Wang JY . Regulation of cell death by the abl tyrosine kinase Oncogene 2000 19: 5643–5650

    CAS  PubMed  Google Scholar 

  37. Lewis JM, Schwartz MA . Integrins regulate the association and phosphorylation of paxillin by c- Abl J Biol Chem 1998 273: 14225–14230

    CAS  PubMed  Google Scholar 

  38. Zipfel PA, Grove M, Blackburn K, Fujimoto M, Tedder TF, Pendergast AM . The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19 J Immunol 2000 165: 6872–6879

    CAS  PubMed  Google Scholar 

  39. Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC . Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene Cell 1991 65: 1153–1163

    CAS  PubMed  Google Scholar 

  40. Voncken JW, van Schaick H, Kaartinen V, Deemer K, Coates T, Landing B, Pattengale P, Dorseuil O, Bokoch GM, Groffen J . Increased neutrophil respiratory burst in bcr-null mutants Cell 1995 80: 719–728

    CAS  PubMed  Google Scholar 

  41. Verfaillie CM . Biology of chronic myelogenous leukemia Hematol Oncol Clin N Am 1998 12: 1–29

    CAS  Google Scholar 

  42. Sawyers CL . Molecular consequences of the BCR-ABL translocation in chronic myelogenous leukemia Leuk Lymphoma 1993 11 (Suppl. 2): 101–103

    Google Scholar 

  43. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM . The biology of chronic myeloid leukemia N Engl J Med 1999 341: 164–172

    CAS  PubMed  Google Scholar 

  44. Thijsen S, Schuurhuis G, van Oostveen J, Ossenkoppele G . Chronic myeloid leukemia from basics to bedside Leukemia 1999 13: 1646–1674

    CAS  PubMed  Google Scholar 

  45. McWhirter JR, Galasso DL, Wang JY . A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins Mol Cell Biol 1993 13: 7587–7595

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Muller AJ, Young JC, Pendergast AM, Pondel M, Landau NR, Littman DR, Witte ON . BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias Mol Cell Biol 1991 11: 1785–1792

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Pendergast AM, Gishizky ML, Havlik MH, Witte ON . SH1 domain autophosphorylation of P210 BCR/ABL is required for transformation but not growth factor independence Mol Cell Biol 1993 13: 1728–1736

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ma G, Lu D, Wu Y, Liu J, Arlinghaus RB . Bcr phosphorylated on tyrosine 177 binds Grb2 Oncogene 1997 14: 2367–2372

    CAS  PubMed  Google Scholar 

  49. Sawyers CL, McLaughlin J, Witte ON . Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene J Exp Med 1995 181: 307–313

    CAS  PubMed  Google Scholar 

  50. Tauchi T, Boswell HS, Leibowitz D, Broxmeyer HE . Coupling between p210bcr-abl and Shc and Grb2 adaptor proteins in hematopoietic cells permits growth factor receptor-independent link to ras activation pathway J Exp Med 1994 179: 167–175

    CAS  PubMed  Google Scholar 

  51. Reuther GW, Fu H, Cripe LD, Collier RJ, Pendergast AM . Association of the protein kinases c-Bcr and Bcr-Abl with proteins of the 14–3-3 family (see comments) Science 1994 266: 129–133

    CAS  PubMed  Google Scholar 

  52. Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA . Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation (see comments) Nature 1993 363: 45–51

    CAS  PubMed  Google Scholar 

  53. Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL . Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia Oncogene 1996 13: 247–254

    CAS  PubMed  Google Scholar 

  54. Ilaria RL, Van Etten RA . P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members J Biol Chem 1996 271: 31704–31710

    CAS  PubMed  Google Scholar 

  55. Carlesso N, Frank DA, Griffin JD . Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl J Exp Med 1996 183: 811–820

    CAS  PubMed  Google Scholar 

  56. Frank DA, Varticovski L . BCR/abl leads to the constitutive activation of Stat proteins, and shares an epitope with tyrosine phosphorylated Stats Leukemia 1996 10: 1724–1730

    CAS  PubMed  Google Scholar 

  57. Carpino N, Wisniewski D, Strife A, Marshak D, Kobayashi R, Stillman B, Clarkson B . p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells Cell 1997 88: 197–204

    CAS  PubMed  Google Scholar 

  58. Jain SK, Langdon WY, Varticovski L . Tyrosine phosphorylation of p120cbl in BCR/abl transformed hematopoietic cells mediates enhanced association with phosphatidylinositol 3-kinase Oncogene 1997 14: 2217–2228

    CAS  PubMed  Google Scholar 

  59. Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, Gewirtz AM, Perussia B, Calabretta B . Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells Blood 1995 86: 726–736

    CAS  PubMed  Google Scholar 

  60. Franke TF, Kaplan DR, Cantley LC . PI3K: downstream AKT ion blocks apoptosis Cell 1997 88: 435–437

    CAS  PubMed  Google Scholar 

  61. Sanchez-Garcia I, Grutz G . Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2 Proc Natl Acad Sci USA 1995 92: 5287–5291

    CAS  PubMed  PubMed Central  Google Scholar 

  62. de Groot RP, Raaijmakers JA, Lammers JW, Koenderman L . STAT5-dependent cyclinD1 and Bcl-xL expression in Bcr-Abl-transformed cells Mol Cell Biol Res Commun 2000 3: 299–305

    CAS  PubMed  Google Scholar 

  63. Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna JL . Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL J Exp Med 2000 191: 977–984

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Van Etten RA, Jackson PK, Baltimore D, Sanders MC, Matsudaira PT, Janmey PA . The COOH terminus of the c-Abl tyrosine kinase contains distinct F- and G-actin binding domains with bundling activity [published erratum appears in J Cell Biol 1994 Mar; 124(5):865] J Cell Biol 1994 124: 325–340

    CAS  PubMed  Google Scholar 

  65. Salgia R, Li JL, Ewaniuk DS, Pear W, Pisick E, Burky SA, Ernst T, Sattler M, Chen LB, Griffin JD . BCR/ABL induces multiple abnormalities of cytoskeletal function J Clin Invest 1997 100: 46–57

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gotoh A, Miyazawa K, Ohyashiki K, Tauchi T, Boswell HS, Broxmeyer HE, Toyama K . Tyrosine phosphorylation and activation of focal adhesion kinase (p125FAK) by BCR-ABL oncoprotein Exp Hematol 1995 23: 1153–1159

    CAS  PubMed  Google Scholar 

  67. Salgia R, Li JL, Lo SH, Brunkhorst B, Kansas GS, Sobhany ES, Sun Y, Pisick E, Hallek M, Ernst T . Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL J Biol Chem 1995 270: 5039–5047

    CAS  PubMed  Google Scholar 

  68. Gordon MY, Dowding CR, Riley GP, Goldman JM, Greaves MF . Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia Nature 1987 328: 342–344

    CAS  PubMed  Google Scholar 

  69. Bhatia R, Verfaillie CM . Inhibition of BCR-ABL expression with antisense oligodeoxynucleotides restores beta1 integrin-mediated adhesion and proliferation inhibition in chronic myelogenous leukemia hematopoietic progenitors Blood 1998 91: 3414–3422

    CAS  PubMed  Google Scholar 

  70. Cortez D, Reuther G, Pendergast AM . The Bcr-Abl tyrosine kinase activates mitogenic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells Oncogene 1997 15: 2333–2342

    CAS  PubMed  Google Scholar 

  71. Harrison-Findik D, Susa M, Varticovski L . Association of phosphatidylinositol 3-kinase with SHC in chronic myelogeneous leukemia cells Oncogene 1995 10: 1385–1391

    CAS  PubMed  Google Scholar 

  72. Korsmeyer SJ . BCL-2 gene family and the regulation of programmed cell death Cancer Res 1999 59 (7 Suppl.): 1693s–1700s

    Google Scholar 

  73. Gesbert F, Griffin JD . Bcr/Abl activates transcription of the Bcl-X gene through STAT5 Blood 2000 96: 2269–2276

    CAS  PubMed  Google Scholar 

  74. Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS, Akhtar AJ, Hilton J, Jones RJ . BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents Blood 1995 86: 1148–1158

    CAS  PubMed  Google Scholar 

  75. Cortez D, Kadlec L, Pendergast AM . Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis Mol Cell Biol 1995 15: 5531–5541

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Nishii K, Kabarowski JH, Gibbons DL, Griffiths SD, Titley I, Wiedemann LM, Greaves MF . ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block Oncogene 1996 13: 2225–2234

    CAS  PubMed  Google Scholar 

  77. Albrecht T, Schwab R, Henkes M, Peschel C, Huber C, Aulitzky WE . Primary proliferating immature myeloid cells from CML patients are not resistant to induction of apoptosis by DNA damage and growth factor withdrawal Br J Haematol 1996 95: 501–507

    CAS  PubMed  Google Scholar 

  78. Amos TA, Lewis JL, Grand FH, Gooding RP, Goldman JM, Gordon MY . Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids Br J Haematol 1995 91: 387–393

    CAS  PubMed  Google Scholar 

  79. Cotter TG . BCR-ABL: an anti-apoptosis gene in chronic myelogenous leukemia Leuk Lymphoma 1995 18: 231–236

    CAS  PubMed  Google Scholar 

  80. Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ . Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia Blood 1994 83: 2038–2044

    CAS  PubMed  Google Scholar 

  81. McGahon A, Bissonnette R, Schmitt M, Cotter KM, Green DR, Cotter TG . BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death [published erratum appears in Blood 1994 Jun 15;83(12):3835] Blood 1994 83: 1179–1187

    CAS  PubMed  Google Scholar 

  82. Amarante-Mendes GP, Naekyung Kim C, Liu L, Huang Y, Perkins CL, Green DR, Bhalla K . Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3 Blood 1998 91: 1700–1705

    CAS  PubMed  Google Scholar 

  83. Dubrez L, Eymin B, Sordet O, Droin N, Turhan AG, Solary E . BCR-ABL delays apoptosis upstream of procaspase-3 activation Blood 1998 91: 2415–2422

    CAS  PubMed  Google Scholar 

  84. Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS Jr . A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation Genes Dev 1998 12: 968–981

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Sanchez-Garcia I, Martin-Zanca D . Regulation of Bcl-2 gene expression by BCR-ABL is mediated by Ras J Mol Biol 1997 267: 225–228

    CAS  PubMed  Google Scholar 

  86. Cortez D, Stoica G, Pierce JH, Pendergast AM . The BCR-ABL tyrosine kinase inhibits apoptosis by activating a Ras-dependent signaling pathway Oncogene 1996 13: 2589–2594

    CAS  PubMed  Google Scholar 

  87. Kinoshita T, Yokota T, Arai K, Miyajima A . Suppression of apoptotic death in hematopoietic cells by signalling through the IL-3/GM-CSF receptors EMBO J 1995 14: 266–275

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Gisslinger H, Kurzrock R, Wetzler M, Tucker S, Kantarjian H, Robertson B, Talpaz M . Apoptosis in chronic myelogenous leukemia: studies of stage-specific differences Leuk Lymphoma 1997 25: 121–133

    CAS  PubMed  Google Scholar 

  89. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344: 1031–1037

    CAS  PubMed  Google Scholar 

  90. Vigneri P, Wang JY . Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase Nat Med 2001 7: 228–234

    CAS  PubMed  Google Scholar 

  91. Cambier N, Chopra R, Strasser A, Metcalf D, Elefanty AG . BCR-ABL activates pathways mediating cytokine independence and protection against apoptosis in murine hematopoietic cells in a dose-dependent manner Oncogene 1998 16: 335–348

    CAS  PubMed  Google Scholar 

  92. Gaiger A, Henn T, Horth E, Geissler K, Mitterbauer G, Maier-Dobersberger T, Greinix H, Mannhalter C, Haas OA, Lechner K . Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression Blood 1995 86: 2371–2378

    CAS  PubMed  Google Scholar 

  93. Wetzler M, Talpaz M, Van Etten RA, Hirsh-Ginsberg C, Beran M, Kurzrock R . Subcellular localization of Bcr, Abl, and Bcr-Abl proteins in normal and leukemic cells and correlation of expression with myeloid differentiation J Clin Invest 1993 92: 1925–1939

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wetzler M, Talpaz M, Estrov Z, Kurzrock R . CML: mechanisms of disease initiation and progression Leuk Lymphoma 1993 11 (Suppl. 1): 47–50

    Google Scholar 

  95. Gordon MY, Dazzi F, Marley SB, Lewis JL, Nguyen D, Grand FH, Davidson RJ, Goldman JM . Cell biology of CML cells Leukemia 1999 13 (Suppl. 1): S65–S71

    Google Scholar 

  96. Sachs L . The control of hematopoiesis and leukemia: from basic biology to the clinic Proc Natl Acad Sci USA 1996 93: 4742–4749

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Eisbruch A, Blick M, Evinger-Hodges MJ, Beran M, Andersson B, Gutterman JU, Kurzrock R . Effect of differentiation-inducing agents on oncogene expression in a chronic myelogenous leukemia cell line Cancer 1988 62: 1171–1178

    CAS  PubMed  Google Scholar 

  98. Lim SH, Coleman S . Chronic myeloid leukemia as an immunological target Am J Hematol 1997 54: 61–67

    CAS  PubMed  Google Scholar 

  99. Selleri C, Maciejewski JP . The role of FAS-mediated apoptosis in chronic myelogenous leukemia Leuk Lymphoma 2000 37: 283–297

    CAS  PubMed  Google Scholar 

  100. Lickliter JD, Kratzke RA, Nguyen PL, Niehans GA, Miller JS . Fas ligand is highly expressed in acute leukemia and during the transformation of chronic myeloid leukemia to blast crisis Exp Hematol 1999 27: 1519–1527

    CAS  PubMed  Google Scholar 

  101. Pierson BA, Miller JS . The role of autologous natural killer cells in chronic myelogenous leukemia Leuk Lymphoma 1997 27: 387–399

    CAS  PubMed  Google Scholar 

  102. Pierson BA, Miller JS . CD56+bright and CD56+dim natural killer cells in patients with chronic myelogenous leukemia progressively decrease in number, respond less to stimuli that recruit clonogenic natural killer cells, and exhibit decreased proliferation on a per cell basis Blood 1996 88: 2279–2287

    CAS  PubMed  Google Scholar 

  103. Gambacorti-Passerini C, Barni R, Marchesi E, Verga M, Rossi F, Pioltelli P, Pogliani E, Marco Corneo G . Sensitivity to the abl inhibitor STI571 in fresh leukaemic cells obtained from chronic myelogenous leukaemia patients in different stages of disease Br J Haematol 2001 112: 972–974

    CAS  PubMed  Google Scholar 

  104. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV . Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance Blood 2000 96: 1070–1079

    CAS  PubMed  Google Scholar 

  105. Turkina AG, Logacheva NP, Stromskaya TP, Zabotina TN, Kuznetzov SV, Sachibzadaeva KK, Tagiev A, Juravlev VS, Khoroshko ND, Baryshnikov AY, Stavrovskaya AA . Studies of some mechanisms of drug resistance in chronic myeloid leukemia (CML) Adv Exp Med Biol 1999 457: 477–488

    CAS  PubMed  Google Scholar 

  106. Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L, Rossi F, Gianazza E, Brueggen J, Cozens R, Pioltelli P, Pogliani E, Corneo G, Formelli F, D'Incalci M . Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR- ABL(+) leukemic cells to the abl inhibitor STI571 J Natl Cancer Inst 2000 92: 1641–1650

    CAS  PubMed  Google Scholar 

  107. Weisberg E, Griffin JD . Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines Blood 2000 95: 3498–3505

    CAS  PubMed  Google Scholar 

  108. Mitelman F . The cytogenetic scenario of chronic myeloid leukemia Leuk Lymphoma 1993 11 (Suppl. 1): 11–15

    Google Scholar 

  109. Griesshammer M, Heinze B, Bangerter M, Heimpel H, Fliedner TM . Karyotype abnormalities and their clinical significance in blast crisis of chronic myeloid leukemia J Mol Med 1997 75: 836–838

    CAS  PubMed  Google Scholar 

  110. Ahuja H, Bar-Eli M, Advani SH, Benchimol S, Cline MJ . Alterations in the p53 gene and the clonal evolution of the blast crisis of chronic myelocytic leukemia Proc Natl Acad Sci USA 1989 86: 6783–6787

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Stuppia L, Calabrese G, Peila R, Guanciali-Franchi P, Morizio E, Spadano A, Palka G . p53 loss and point mutations are associated with suppression of apoptosis and progression of CML into myeloid blastic crisis Cancer Genet Cytogenet 1997 98: 28–35

    CAS  PubMed  Google Scholar 

  112. Mashal R, Shtalrid M, Talpaz M, Kantarjian H, Smith L, Beran M, Cork A, Trujillo J, Gutterman J, Deisseroth A . Rearrangement and expression of p53 in the chronic phase and blast crisis of chronic myelogenous leukemia Blood 1990 75: 180–189

    CAS  PubMed  Google Scholar 

  113. Sill H, Goldman JM, Cross NC . Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia Blood 1995 85: 2013–2016

    CAS  PubMed  Google Scholar 

  114. Ahuja HG, Jat PS, Foti A, Bar-Eli M, Cline MJ . Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia Blood 1991 78: 3259–3268

    CAS  PubMed  Google Scholar 

  115. Karasawa M, Okamoto K, Maehara T, Tsukamoto N, Morita K, Naruse T, Omine M . Detection of c-myc oncogene amplification in a CML blastic phase patient with double minute chromosomes Leuk Res 1996 20: 85–91

    CAS  PubMed  Google Scholar 

  116. Gopal V, Kadam P, Preisler H, Hulette B, Li YQ, Steele P, Freeman J, Banavali S . Abnormal regulation of the myc gene in myeloid leukemia Med Oncol Tumor Pharmacother 1992 9: 139–147

    CAS  PubMed  Google Scholar 

  117. Preisler HD, Agarwal R, Sato H, Singh PK, Wang ZQ, Sandberg AA . Studies of proto-oncogene expression in the chronic and blastic phases of chronic myelogenous leukemia Eur J Cancer 1990 26: 960–965

    CAS  PubMed  Google Scholar 

  118. Kaida S, Fujikawa T, Endou S, Inaba S, Nagayama Y, Sakato H, Yamazaki Y, Sano S, Tanaka N, Yamada H . The changes of mRNAs of both c-myc and MDR1 in CML-bc tumor cells during the clinical course: a case report Rinsho Ketsueki 1989 30: 697–701

    CAS  PubMed  Google Scholar 

  119. Liu E, Hjelle B, Bishop JM . Transforming genes in chronic myelogenous leukemia Proc Natl Acad Sci USA 1988 85: 1952–1956

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, Yazaki Y, Ohki M, Hirai H . Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia EMBO J 1994 13: 504–510

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Mitani K, Miyazono K, Urabe A, Takaku F . Karyotypic changes during the course of blastic crisis of chronic myelogenous leukemia Cancer Genet Cytogenet 1989 39: 299–300

    CAS  PubMed  Google Scholar 

  122. Hoekstra MF . Responses to DNA damage and regulation of cell cycle checkpoints by the ATM protein kinase family Curr Opin Genet Dev 1997 7: 170–175

    CAS  PubMed  Google Scholar 

  123. Miyashita T, Reed JC . Tumor suppressor p53 is a direct transcriptional activator of the human bax gene Cell 1995 80: 293–299

    CAS  PubMed  Google Scholar 

  124. Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P . Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis Science 1998 282: 290–293

    CAS  PubMed  Google Scholar 

  125. Wu GS, Burns TF, McDonald ER, Meng RD, Kao G, Muschel R, Yen T, el-Deiry WS . Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest Oncogene 1999 18: 6411–6418

    CAS  PubMed  Google Scholar 

  126. Levine AJ . p53, the cellular gatekeeper for growth and division Cell 1997 88: 323–331

    CAS  PubMed  Google Scholar 

  127. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A . Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours Nature 1992 356: 215–221

    CAS  PubMed  Google Scholar 

  128. Lanza F, Bi S . Role of p53 in leukemogenesis of chronic myeloid leukemia Stem Cells 1995 13: 445–452

    CAS  PubMed  Google Scholar 

  129. Foti A, Bar-Eli M, Ahuja HG, Cline MJ . A splicing mutation accounts for the lack of p53 gene expression in a CML blast crisis cell line: a novel mechanism of p53 gene inactivation Br J Haematol 1990 76: 143–145

    CAS  PubMed  Google Scholar 

  130. Fioretos T, Strombeck B, Sandberg T, Johansson B, Billstrom R, Borg A, Nilsson PG, Van Den Berghe H, Hagemeijer A, Mitelman F, Hoglund M . Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations Blood 1999 94: 225–232

    CAS  PubMed  Google Scholar 

  131. Ahuja H, Bar-Eli M, Arlin Z, Advani S, Allen SL, Goldman J, Snyder D, Foti A, Cline M . The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia J Clin Invest 1991 87: 2042–2047

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Hernandez-Boluda JC, Cervantes F, Costa D, Carrio A, Montserrat E . Blast crisis of Ph-positive chronic myeloid leukemia with isochromosome 17q: report of 12 cases and review of the literature Leuk Lymphoma 2000 38: 83–90

    CAS  PubMed  Google Scholar 

  133. Bi S, Barton CM, Lemoine NR, Cross NC, Goldman JM . Retroviral transduction of Philadelphia-positive chronic myeloid leukemia cells with a human mutant p53 cDNA and its effect on in vitro proliferation (see comments) Exp Hematol 1994 22: 95–99

    CAS  PubMed  Google Scholar 

  134. Honda H, Ushijima T, Wakazono K, Oda H, Tanaka Y, Aizawa S, Ishikawa T, Yazaki Y, Hirai H . Acquired loss of p53 induces blastic transformation in p210(bcr/abl)-expressing hematopoietic cells: a transgenic study for blast crisis of human CML Blood 2000 95: 1144–1150

    CAS  PubMed  Google Scholar 

  135. Skorski T, Nieborowska-Skorska M, Wlodarski P, Perrotti D, Martinez R, Wasik MA, Calabretta B . Blastic transformation of p53-deficient bone marrow cells by p210bcr/abl tyrosine kinase Proc Natl Acad Sci USA 1996 93: 13137–13142

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Foti A, Ahuja HG, Allen SL, Koduru P, Schuster MW, Schulman P, Bar-Eli M, Cline MJ . Correlation between molecular and clinical events in the evolution of chronic myelocytic leukemia to blast crisis Blood 1991 77: 2441–2444

    CAS  PubMed  Google Scholar 

  137. Ishikura H, Yufu Y, Yamashita S, Abe Y, Okamura T, Motomura S, Nishimura J, Nawata H . Biphenotypic blast crisis of chronic myelogenous leukemia: abnormalities of p53 and retinoblastoma genes Leuk Lymphoma 1997 25: 573–578

    CAS  PubMed  Google Scholar 

  138. Serra A, Gottardi E, Della Ragione F, Saglio G, Iolascon A . Involvement of the cyclin-dependent kinase-4 inhibitor (CDKN2) gene in the pathogenesis of lymphoid blast crisis of chronic myelogenous leukaemia Br J Haematol 1995 91: 625–629

    CAS  PubMed  Google Scholar 

  139. Quesnel B, Preudhomme C, Fenaux P . p16ink4a gene and hematological malignancies Leuk Lymphoma 1996 22: 11–24

    CAS  PubMed  Google Scholar 

  140. Drexler HG . Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia–lymphoma cells Leukemia 1998 12: 845–859

    CAS  PubMed  Google Scholar 

  141. Asimakopoulos FA, Shteper PJ, Krichevsky S, Fibach E, Polliack A, Rachmilewitz E, Ben-Neriah Y, Ben-Yehuda D . ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia Blood 1999 94: 2452–2460

    CAS  PubMed  Google Scholar 

  142. Ben-Yehuda D, Krichevsky S, Rachmilewitz EA, Avraham A, Palumbo GA, Frassoni F, Sahar D, Rosenbaum H, Paltiel O, Zion M, Ben-Neriah Y . Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia Blood 1997 90: 4918–4923

    CAS  PubMed  Google Scholar 

  143. Issa JP, Kantarjian H, Mohan A, O'Brien S, Cortes J, Pierce S, Talpaz M . Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic significance (see comments) Blood 1999 93: 2075–2080

    CAS  PubMed  Google Scholar 

  144. Zion M, Ben-Yehuda D, Avraham A, Cohen O, Wetzler M, Melloul D, Ben-Neriah Y . Progressive de novo DNA methylation at the bcr-abl locus in the course of chronic myelogenous leukemia Proc Natl Acad Sci USA 1994 91: 10722–10726

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Malinen T, Palotie A, Pakkala S, Peltonen L, Ruutu T, Jansson SE . Acceleration of chronic myeloid leukemia correlates with calcitonin gene hypermethylation Blood 1991 77: 2435–2440

    CAS  PubMed  Google Scholar 

  146. Popenoe DW, Schaefer-Rego K, Mears JG, Bank A, Leibowitz D . Frequent and extensive deletion during the 9,22 translocation in CML Blood 1986 68: 1123–1128

    CAS  PubMed  Google Scholar 

  147. Shtalrid M, Talpaz M, Kurzrock R, Kantarjian H, Trujillo J, Gutterman J, Yoffe G, Blick M . Analysis of breakpoints within the bcr gene and their correlation with the clinical course of Philadelphia-positive chronic myelogenous leukemia Blood 1988 72: 485–490

    CAS  PubMed  Google Scholar 

  148. Sinclair PB, Nacheva EP, Leversha M, Telford N, Chang J, Reid A, Bench A, Champion K, Huntly B, Green AR . Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia Blood 2000 95: 738–743

    CAS  PubMed  Google Scholar 

  149. Nakayama H, Ishimaru F, Avitahl N, Sezaki N, Fujii N, Nakase K, Ninomiya Y, Harashima A, Minowada J, Tsuchiyama J, Imajoh K, Tsubota T, Fukuda S, Sezaki T, Kojima K, Hara M, Takimoto H, Yorimitsu S, Takahashi I, Miyata A, Taniguchi S, Tokunaga Y, Gondo H, Niho Y, Harada M . Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia Cancer Res 1999 59: 3931–3934

    CAS  PubMed  Google Scholar 

  150. Randhawa GS, Cui H, Barletta JA, Strichman-Almashanu LZ, Talpaz M, Kantarjian H, Deisseroth AB, Champlin RC, Feinberg AP . Loss of imprinting in disease progression in chronic myelogenous leukemia Blood 1998 91: 3144–3147

    CAS  PubMed  Google Scholar 

  151. Majlis A, Smith TL, Talpaz M, O'Brien S, Rios MB, Kantarjian HM . Significance of cytogenetic clonal evolution in chronic myelogenous leukemia J Clin Oncol 1996 14: 196–203

    CAS  PubMed  Google Scholar 

  152. Afar DE, Goga A, McLaughlin J, Witte ON, Sawyers CL . Differential complementation of Bcr-Abl point mutants with c-Myc Science 1994 264: 424–426

    CAS  PubMed  Google Scholar 

  153. Skorski T, Perrotti D, Nieborowska-Skorska M, Gryaznov S, Calabretta B . Antileukemia effect of c-myc N3′-→P5′ phosphoramidate antisense oligonucleotides in vivo Proc Natl Acad Sci USA 1997 94: 3966–3971

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Skorski T, Nieborowska-Skorska M, Wlodarski P, Zon G, Iozzo RV, Calabretta B . Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous leukemia blast crisis in SCID mice Blood 1996 88: 1005–1012

    CAS  PubMed  Google Scholar 

  155. Handa H, Hegde UP, Kotelnikov VM, Mundle SD, Dong LM, Burke P, Rose S, Gaskin F, Raza A, Preisler HD . Bcl-2 and c-myc expression, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase Leuk Res 1997 21: 479–489

    CAS  PubMed  Google Scholar 

  156. Daheron L, Salmeron S, Patri S, Brizard A, Guilhot F, Chomel JC, Kitzis A . Identification of several genes differentially expressed during progression of chronic myelogenous leukemia Leukemia 1998 12: 326–332

    CAS  PubMed  Google Scholar 

  157. Ceballos E, Delgado MD, Gutierrez P, Richard C, Muller D, Eilers M, Ehinger M, Gullberg U, Leon J . c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells Oncogene 2000 19: 2194–2204

    CAS  PubMed  Google Scholar 

  158. Blick M, Romero P, Talpaz M, Kurzrock R, Shtalrid M, Andersson B, Trujillo J, Beran M, Gutterman J . Molecular characteristics of chronic myelogenous leukemia in blast crisis Cancer Genet Cytogenet 1987 27: 349–356

    CAS  PubMed  Google Scholar 

  159. Ogawa S, Kurokawa M, Tanaka T, Mitani K, Inazawa J, Hangaishi A, Tanaka K, Matsuo Y, Minowada J, Tsubota T, Yazaki Y, Hirai H . Structurally altered Evi-1 protein generated in the 3q21q26 syndrome Oncogene 1996 13: 183–191

    CAS  PubMed  Google Scholar 

  160. Ogawa S, Kurokawa M, Tanaka T, Tanaka K, Hangaishi A, Mitani K, Kamada N, Yazaki Y, Hirai H . Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia Leukemia 1996 10: 788–794

    CAS  PubMed  Google Scholar 

  161. Ohyashiki K, Ohyashiki JH, Fujieda H, Shimamoto T, Kawakubo K, Nakazawa S, Suzukawa K, Morishita K, Toyama K . EVI1 expression associated with a 3q26 anomaly in a leukemia cell line derived from the blast crisis of chronic myeloid leukemia Leukemia 1994 8: 2169–2173

    CAS  PubMed  Google Scholar 

  162. Mitani K . Molecular mechanism of blastic crisis in chronic myelocytic leukemia Leukemia 1997 11 (Suppl. 3): 503–505

    Google Scholar 

  163. Goga A, McLaughlin J, Afar DE, Saffran DC, Witte ON . Alternative signals to RAS for hematopoietic transformation by the BCR- ABL oncogene Cell 1995 82: 981–988

    CAS  PubMed  Google Scholar 

  164. Mandanas RA, Leibowitz DS, Gharehbaghi K, Tauchi T, Burgess GS, Miyazawa K, Jayaram HN, Boswell HS . Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells Blood 1993 82: 1838–1847

    CAS  PubMed  Google Scholar 

  165. Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T . Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway EMBO J 1994 13: 764–773

    CAS  PubMed  PubMed Central  Google Scholar 

  166. LeMaistre A, Lee MS, Talpaz M, Kantarjian HM, Freireich EJ, Deisseroth AB, Trujillo JM, Stass SA . Ras oncogene mutations are rare late stage events in chronic myelogenous leukemia Blood 1989 73: 889–891

    CAS  PubMed  Google Scholar 

  167. Watzinger F, Gaiger A, Karlic H, Becher R, Pillwein K, Lion T . Absence of N-ras mutations in myeloid and lymphoid blast crisis of chronic myeloid leukemia Cancer Res 1994 54: 3934–3938

    CAS  PubMed  Google Scholar 

  168. Mori N, Takeuchi S, Tasaka T, Lee S, Spira S, Ben-Yehuda D, Mizoguchi H, Schiller G, Koeffler HP . Absence of microsatellite instability during the progression of chronic myelocytic leukemia Leukemia 1997 11: 151–152

    CAS  PubMed  Google Scholar 

  169. Wada C, Shionoya S, Fujino Y, Tokuhiro H, Akahoshi T, Uchida T, Ohtani H . Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia (see comments) Blood 1994 83: 3449–3456

    CAS  PubMed  Google Scholar 

  170. Guinn BA, Mills KI . p53 mutations, methylation and genomic instability in the progression of chronic myeloid leukaemia Leuk Lymphoma 1997 26: 211–226

    CAS  PubMed  Google Scholar 

  171. Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG Jr, Levrero M, Wang JY . The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage Nature 1999 399: 806–809

    CAS  PubMed  Google Scholar 

  172. Deutsch E, Dugray A, AbdulKarim B, Marangoni E, Maggiorella L, Vaganay S, M'Kacher R, Rasy SD, Eschwege F, Vainchenker W, Turhan AG, Bourhis J . BCR-ABL down-regulates the DNA repair protein DNA-PKcs Blood 2001 97: 2084–2090

    CAS  PubMed  Google Scholar 

  173. Mitelmann F . Catalogue of Chromosomal Aberrations. Cancer 1991, 4th edn Wiley Lewis: New York 1991

    Google Scholar 

  174. Raitano AB, Halpern JR, Hambuch TM, Sawyers CL . The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation Proc Natl Acad Sci USA 1995 92: 1174–1175

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shet, A., Jahagirdar, B. & Verfaillie, C. Chronic myelogenous leukemia: mechanisms underlying disease progression. Leukemia 16, 1402–1411 (2002). https://doi.org/10.1038/sj.leu.2402577

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402577

Keywords

This article is cited by

Search

Quick links