Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia

Nature Reviews Cancer

Volumn 5, Issue 3, 2005, Pages 172-183

  Ren, Ruibao ^a  

^a BRANDEIS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BCR ABL PROTEIN; IMATINIB; PROTEIN TYROSINE KINASE INHIBITOR;

ANTINEOPLASTIC ACTIVITY; CANCER MODEL; CANCER RESISTANCE; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; DRUG POTENCY; ENZYME ACTIVITY; HUMAN; HUMAN CELL; LEUKEMOGENESIS; MOUSE; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL TRANSFORMATION, NEOPLASTIC; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION, NEOPLASTIC; GENES, ABL; HUMANS; LEUKEMIA, MYELOID, CHRONIC; MICE; ONCOGENE PROTEINS V-ABL; PIPERAZINES; PROTO-ONCOGENE PROTEINS C-ABL; PYRIMIDINES;

EID: 14644425319     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1567     Document Type: Review

References (121)

1. Kurzrock, R., Gutterman, J. & Talpaz, M. The molecular genetics of Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 319, 990-998 (1988).
2. Goldman, J. M. & Druker, B. J. Chronic myeloid leukemia: current treatment options. Blood 98, 2039-2042 (2001).
3. Deininger, M., Buchdunger, E. & Druker, B. J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 23 Dec 2004 (doi: 10.1182/blood-2004-08-3097).
4. Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 2, 561-566 (1996).
5. Deininger, M. W., Goldman, J. M., Lydon, N. & Melo, J. V. The tyrosine kinase inhibtor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90, 3691-3698 (1997).
6. Deininger, M. W. et al. BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res. 60, 2049-2055 (2000).
7. le Coutre, P. et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J. Natl Cancer Inst. 91, 163-168 (1999).
8. Druker, B. J., O'Brien, S. G., Cortes, J. & Radich, J. Chronic myelogenous leukemia. Hematology (Am. Soc. Hematol. Educ. Program) 111-135 (2002).
9. Stentoft, J. et al. Kinetics of BCR-ABL fusion transcript levels in chronic myeloid leukemia patients treated with STI571 measured by quantitative real-time polymerase chain reaction. Eur. J. Haematol. 67, 302-308 (2001).
10. Bhatia, R. et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101, 4701-4707 (2003).
11. Lowenberg, B. Minimal residual disease in chronic myeloid leukemia. N. Engl. J. Med. 349, 1399-1401 (2003).
12. Gorre, M. E. & Sawyers, C. L. Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr. Opin. Hematol. 9, 303-307 (2002). A comprehensive review on the molecular mechanisms of imatinib resistance in CML.
13. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876-880 (2001).
14. Weisberg, E. & Griffin, J. D. Resistance to imatinib (Glivec): update on clinical mechanisms. Drug Resist. Updat. 6, 231-238 (2003).
15. Woodring, P. J., Hunter, T. & Wang, J. Y. Regulation of F-actin-dependent processes by the Abl family of tyrosine kinases. J. Cell Sci. 116, 2613-2626 (2003).
16. Hernandez, S. E., Krishnaswami, M., Miller, A. L. & Koleske, A. J. How do Abl family kinases regulate cell shape and movement? Trends Cell Biol. 14, 36-44 (2004).
17. Schwartzberg, P. L. et al. Mice homozygous for the ablm1 mutation show poor viaility and depletion of selected B and T cell populations. Cell 65, 1165-1175 (1991).
18. Tybulewicz, V. L. J., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153-1163 (1991).
19. Koleske, A. J. et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 21, 1259-1272 (1998).
20. Voncken, J. W. et al. Increased neutrophil respiratory burst in bcr-null mutants. Cell 80, 719-728 (1995).
21. Ren, R. The molecular mechanism of chronic myelogenous leukemia and its therapeutic implications: studies in a murine model. Oncogene 21, 8629-8642 (2002).
22. Ramaraj, P. et al. Effect of mutational inactivation of tyrosine kinase activity on BCR/ABL-induced abnormalities in cell growth and adhesion in human hematopoietic progenitors. Cancer Res. 64, 5322-5331 (2004).
23. + cells with a BCR/ABL-containing retroviral vector. Blood 97, 2406-2412 (2001).
24. Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824-830 (1990).
25. Kelliher, M. A., McLaughlin, J., Witte, O. N. & Rosenberg, N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc. Natl Acad. Sci. USA 87, 6649-6653 (1990).
26. Elefanty, A. G., Hariharan, I. K. & Cory, S. bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice. EMBO J. 9, 1069-1078 (1990).
27. Hawley, R. G. High-titer retroviral vectors for efficient transduction of functional genes into murine hematopoietic stem cells. Ann. NY Acad. Sci. 716, 327-330 (1994).
28. Cherry, S. R., Biniszkiewicz, D., van Parijs, L., Baltimore, D. & Jaenisch, R. Retroviral expression in embryonic stem cells and hematopoetic stem cells. Mol. Cell. Biol. 20, 7419-7426 (2000).
29. Zhang, X. & Ren, R. Bcr-Abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia. Blood 92, 3829-3840 (1998).
30. Pear, W. S. et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receding P210 bcr/abl-transduced bone marrow. Blood 92, 3780-3792 (1998).
31. Li, S., Ilaria, R. L., Million, R. P., Daley, G. Q. & Van Etten, R. A. 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. 189, 1399-1412 (1999).
32. Heisterkamp, N., Jenster, G., Kioussis, D., Pattengale, P. K. & Groffen, J. Human bcr-abl gene has a lethal effect on embryogenesis. Transgenic Res. 1, 45-53 (1991).
33. Castellanos, A. et al. A BCR-ABL(p190) fusion gene made by homologous recombination causes B-cell acute lymphoblastic leukemias in chimeric mice with independence of the endogenous bcr product. Blood 90, 2168-2174 (1997).
34. Heisterkamp, N. et al. Acute leukemia in bcr/abl transgenic mice. Nature 344, 251-253 (1990).
35. Voncken, J. W. et al. Restricted oncogenicity of BCR/ABL p190 in transgenic mice. Cancer Res. 52, 4534-4539 (1992).
36. Voncken, J. W. et al. BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice. Blood 86, 4603-4611 (1995).
37. Honda, H. et al. Expression of p210bcr-abl by metallothionein promoter induced T-cell leukemia in transgenic mice. Blood 85, 2853-2861 (1995).
38. Huettner, C. S., Zhang, P., Van Etten, R. A. & Tenen, D. G. Reveribility of acute B-cell leukemia induced by BCR-ABL1. Nature Genet. 24, 57-60 (2000).
39. Huettner, C. S. et al. Inducible expression of BCR/ABL using human CD34 regulatory elements results in a megakaryocytic myeloproliferative syndrome. Blood 102, 3363-3370 (2003).
40. Koschmieder, S. et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukaemogenesis. Blood 105, 324-334 (2005).
41. Faderl, S. et al. The biology of chronic myeloid leukemia. N. Engl. J. Med. 341, 164-172 (1999).
42. Deininger, M. W., Goldman, J. M. & Melo, J. V. The molecular biology of chronic myeloid leukemia. Blood 96, 3343-3356 (2000).
43. Ahuja, H. G., Popplewell, L., Tcheurekdjian, L. & Slovak, M. L. NUP98 gene rearrangements and the clonal evolution of chronic myelogenous leukemia. Genes Chromosom. Cancer 30, 410-415 (2001).
44. Colovic, M., Jankovic, G., Bila, J., Djordjevic, V. & Wiernik, R H. Inversion of chromosome 16 in accelerated phase of chronic myeloid leukaemia: report of a case and review of the literature. Med. Oncol. 15, 199-201 (1998).
45. de Bruijn, M. F. & Speck, N. A. Core-binding factors in hematopoiesis and immune function. Oncogene 23, 4238-4248 (2004).
46. Hirai, H. The transcription factor Evi-1. Int. J. Biochem. Cell Biol. 31, 1367-1371 (1999).
47. Ihle, J. N., Morishita, K., Matsugi, T. & Bartholomew, C. Insertional mutagenesis and transformation of hematopoietic stem cells. Prog. Clin. Biol. Res. 352, 329-337 (1990).
48. Cuenco, G. M., Nucifora, G. & Ren, R. Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a novel model for human AML. Proc. Natl Acad. Sci. USA 97, 1760-1765 (2000).
49. Cuenco, G. M. & Ren, R. Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia. Oncogens 20, 8236-8248 (2001). The first report of cooperation of BCR-ABL and an oncogenic transcription factor in induction of a myeloblastic leukaemia in mice. Together, these factors block myeloid differentiation, transforming CML from the chronic phase to blast phase.
50. Dash, A. B. et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc. Natl Acad. Sci. USA 99, 7622-7627 (2002).
51. Jamieson, C. H. et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657-667 (2004). Reported that GMPs in blast-phase CML undergo self renewal. The results indicate that GMPs are transformed into leukaemic stem cells during blast-phase CML.
52. Ghaffari, S., Daley, G. Q. & Lodish, H. F. Growth factor independence and BCR/ABL transformation: promise and pitfalls of murine model systems and assays. Leukemia 13, 1200-1206 (1999).
53. Ren, R. Modeling the dosage effect of oncogenes in leukaemogenesis. Curr. Opin. Hematol. 11, 25-34 (2004).
54. Gross, A. W., Zhang, X. & Ren, R. Bcr-Abl with an SH3 deletion retains the ability to induce a myeloproliferative deease in mice, yet c-Abl activated by an sh3 deletion induces only lymphoid malignancy. Mol. Cell Biol. 19, 6918-6928 (1999). Showed that activation of the ABL kinase activity is not sufficient for BCR-ABL to induce CML-like disease in mice.
55. Gross, A. W. & Ren, R. Bcr-Abl has a greater intrinsic capacity than v-Abl to induce the neoplastic expansion of myeloid cells in vivo. Oncogene 19, 6286-6296 (2000).
56. McWhirter, J. R., Gaalasso, D. L. & Wang, J. Y. J. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol. Cell. Biol. 13, 7587-7595 (1993).
57. Zhang, X., Subrahmanyam, R., Wong, R., Gross, A. W. & Ren, R. The NH2-terminal coiled-coil domain and tyrosine 177 play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl. Mol. Cell. Biol. 21, 840-853 (2001).
58. He, Y. et al. The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl. Blood 99, 2957-5768 (2002).
59. Smith, K. M., Yacobi, R. & Van Etten, R. A. Autoinhibition of Bcr-Abl through its SH3 domain. Mol. Cell 12, 27-37 (2003).
60. Pendergast, A. M. et al. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the Grb-2 adaptor protein. Cell 75, 175-185 (1993).
61. Puil, L. et al. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J. 13, 764-773 (1994).
62. Sattler, M. et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 1, 479-492 (2002). Described the critical role of GAB2 in mediating the ability of BCR-ABL to confer cytokine-independent growth of primary myeloid cells.
63. Million, R. P. & Van Etten, R. A. The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase. Blood 96, 664-670 (2000).
64. Goga, A., McLaughlin, J., Afar, D. E., Saffran, D. C. & Witte, O. N. Alternative signals to RAS for hematopoietic transformation by the Bcr-Abl oncogene. Cell 82, 981-988 (1995).
65. Zhang, X., Wong, R., Hao, S. X., Pear, W. S. & Ren, R. The SH2 domain of bcr-Abl is not required to induce a murine myeloproliferative disease; however, SH2 signaling influences disease latency and phenotype. Blood 97, 277-287 (2001).
66. Roumiantsev, S., de Aos, I. E., Varticovski, L., Ilaria, R. L. & Van Etten, R. A. The src homology 2 domain of Bcr/Abl is required for efficient induction of chronic myeloid leukemia-like disease in mice but not for lymphoid leukaemogenesis or activation of phosphatidylinositol 3-kinase. Blood 97, 4-13 (2001).
67. Prywes, R., Foulkes, J. G., Rosenberg, N. & Baltimore, D. Sequences of the A-MuLV protein needed for fibroblast and lymphoid cell transformation. Cell 34, 569-579 (1983).
68. Wertheim, J. A. et al. Localization of BCR-ABL to F-actin regulates cell adhesion but does not attenuate CML development. Blood 102, 2220-2228 (2003).
69. Dai, Z., Kerzic, P., Schroeder, W. G. & McNiece, I. K. Deletion of the Src homology 3 domain and C-terminal proline-rich sequences in Bcr-Abl prevents Abl interactor 2 degradation and spontaneous cell migration and impairs leukaemogenesis. J. Biol. Chem. 276, 28954-28960 (2001).
70. Nieborowska-Skorska, M., Hoser, G., Kossev, P., Wasik, M. A. & Skorski, T. Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukaemogenesis. Blood 99, 4531-4539 (2002).
71. Wong, S. & Witte, O. N. The BCR-ABL story: bench to bedside and back. Annu. Rev. Immunol. 22, 247-306 (2004).
72. Jiang, X., Lopez, A., Holyoake, T., Eaves, A. & Eaves, C. Autocrine production and action of IL-3 and granulocyte colony- stimulating factor in chronic myeloid leukemia. Proc. Natl Acad. Sci. USA 96, 12804-12809 (1999).
73. Sexl, V. et al. Stat5a/b contribute to interleukin 7-induced B-cell precursor expansion, but abl- and bcr/abl-induced transformation are independent of stat5. Blood 96, 2277-2283 (2000).
74. Dinulescu, D. M. et al. c-CBL is not required for leukemia induction by Bcr-Abl in mice. Oncogene 22, 8852-8860 (2003).
75. Li, S. et al. Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL. Blood 97, 1442-1450 (2001).
76. Hu, Y. et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nature Genet. 36, 453-461 (2004).
77. + leukemia cells. Nature Med. 10, 1187-1189 (2004).
78. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nature Rev. Cancer 2, 489-501 (2002).
79. Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genet. 29, 465-468 (2001).
80. Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genet. 34, 148-150 (2003).
81. Kosaki, K. et al. PTPN11 (protein-tyrosine phosphatase, non receptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J. Clin. Endocrinol. Metab. 87, 3529-3533 (2002).
82. Neel, B. G., Gu, H. & Pao, L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284-293 (2003).
83. Bos, J. L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682-4689 (1989).
84. Braun, B. S. et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl Acad. Sci. USA 101, 597-602 (2004).
85. Chan, I. T. et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J. Clin. Invest. 113, 528-538 (2004).
86. Holtschke, T. et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307-317 (1996). Reported the striking discovery that Icsbp-null mice develop of a CML-like disease, indicating that this protein is a tumour suppressor.
87. Tamura, T., Nagamura-Inoue, T., Shmeltzer, Z., Kuwata, T. & Ozato, K. ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 13, 155-165 (2000).
88. Hao, S. X. & Ren, R. Expression of ICSBP is downregulated in Bcr-Abl-induced murine CML-like desease, and forced coexpression of ICSBP inhibits the Bcr-Abl-induced myeloproliferative disorder. Mol. Cell. Biol. 20, 1149-1161 (2000).
89. Schmidt, M. et al. Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood 91, 22-29 (1998).
90. Schorpp-Kistner, M., Wang, Z. Q., Angel, P. & Wagner, E. F. JunB is essential for mammalian placentation. EMBO J. 18, 934-948 (1999).
91. Passegue, E., Jochum, W., Schorpp-Kistner, M., Mohle-Steinlein, U. & Wagner, E. F. Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. Cell 104, 21-32 (2001). Showed that specific inactivation of JUNB in haematopoietic cells led to the development of a CML-like disease in mice. The results indicate that JUNB is a tumour suppressor.
92. Passegue, E., Wagner, E. F. & Weissman, I. L. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119, 431-443 (2004). Reported that induction of CML-like disease by JUNB inactivation only occurs in JUNB-deficient long-term self-renewing haematopoietic stem cells. The results indicated the haematopoietic stem-cell origin of CML.
93. Bruchova, H., Borovanova, T., Klamova, H. & Brdicka, R. Gene expression profiling in chronic myeloid leukemia patients treated with hydroxyurea. Leuk. Lymphoma 43, 1289-1295 (2002).
94. Yang, M. Y., Liu, T. C., Chang, J. G., Lin, P. M. & Lin, S. F. JunB gene expression is inactivated by methylation in chronic myeloid leukemia. Blood 101, 3205-3211 (2003).
95. Ishida, D. et al. Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice. Cancer Cell 4, 55-65 (2003). Described the targeted inactivation of SIPA1, which led to the development of a CML-like disease in mice.
96. Stork, P. J. Does Rap1 deserve a bad Rap? Trends Biochem. Sci. 28, 267-275 (2003).
97. Mizuchi, D. et al. BCR/ABL activates Rap1 and B-Raf to stimulate the MEK/Erk signaling pathway in hematopoietic cells. Biochem. Biophys. Res. Commun. 326, 645-651 (2005).
98. Helgason, C. D. et al. Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev. 12, 1610-1620 (1998).
99. Sattler, M. et al. BCR/ABL directly inhibits expression of SHIP, an SH2-containing polyinositol-5-phosphatase involved in the regulation of hematopoiesis. Mol. Cell. Biol. 19, 7473-7480 (1999).
100. Jiang, X. et al. Evidence for a positive role of SHIP in the BCR-ABL-mediated transformation of primitive murine hematopoietic cells and in human chronic myeloid leukemia. Blood 102, 2976-2984 (2003).
101. Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319-325 (2002).
102. Roche-Lestienne, C. et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100, 1014-1018 (2002).
103. Holtz, M. S. et al. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 99, 3792-3800 (2002).
104. Wertheim, J. A. et al. BCR-ABL-induced adhesion defects are tyrosine kinase-independent. Blood 99, 4122-4130 (2002). Showed that ABL-kinase-deficient BCR-ABL retains the ability to dysregulate cell adhesion.
105. Huntly, B. J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587-596 (2004). Demonstrated that some, but not all, leukaemia-associated oncogenes could confer properties of leukaemic stem cells to haematopoietic progenitors destined to undergo apoptosis.
106. Yoshida, C. & Melo, J. V. Biology of chronic myeloid leukemia and possible therapeutic approaches to imatinib-resistant disease. Int. J. Hematol. 79, 420-433 (2004).
107. Goldman, J. M. Chronic myeloid leukemia-still a few questions. Exp. Hematol. 32, 2-10 (2004).
108. Skorski, T. BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability. Oncogene 21, 8591-8604 (2002).
109. Holyoake, T. L., Jiang, X., Drummond, M. W., Eaves, A. C. & Eaves, C. J. Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia 16, 549-558 (2002).
110. Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399-401 (2004).
111. Sawyers, C.L. et al. Hematologic and cytogenetic responses in Imatinib-resistant chronic phase chronic myelogenous leukemia patients treated with the dual SRC/ABL kinase inhibitor BMS-354825: results from a phase I dose escalation study. Blood 104, 4a (2004).
112. Vigneri, P. & Wang, J. Y. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nature Med. 7, 228-234 (2001).
113. McWhirter, J. R. & Wang, J. Y. J. An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. EMBO J. 12, 1533-1546 (1993).
114. Vickers, M. Estimation of the number of mutations necessary to cause chronic myeloid leukaemia from epidemiological data. Br. J. Haematol. 94, 1-4 (1996).
115. Lichtman, M. Chronic myelogenous leukemia and related disorders. in Williams Hepatology (eds Beutler, E., Lichtman, M. A., Coller, B. S. & Kipps, T. J.) 298-324 (McGraw-Hill, New York, 1995).
116. Biernaux, C., Loos, M., Sels, A., Huez, G. & Stryckmans, P. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 86, 3118-3122 (1995).
117. Bose, S., Deininger, M., Gora-Tybor, J., Goldman, J. M. & Melo, J. V. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 92, 3362-3367 (1998).
118. Takahashi, N., Miura, I., Saitoh, K. & Miura, A. B. Lineage involvement of stem cells bearing the philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence- activated cell sorting and fluorescence in situ hybridization. Blood 92, 4758-4763 (1998).
119. Nagar, B. et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112, 859-871 (2003).
120. Harrison, S. C. Variation on an Src-like theme. Cell 112, 737-740 (2003).
121. Hantschel, O. et al. A myristoyl/phosphotyrosine switch regulates c-Abl. Cell 112, 845-857 (2003).