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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2242-2249. Prepublished online as a Blood First Edition Paper on May 11, 2007; DOI 10.1182/blood-2007-03-066936. This Article Full Text (PDF) All Versions of this Article: blood-2007-03-066936v1 110/7/2242    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by O'Hare, T. Articles by Deininger, M. W. Search for Related Content PubMed PubMed Citation Articles by O'Hare, T. Articles by Deininger, M. W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 21, 2007 Accepted May 7, 2007 Bcr-Abl kinase domain mutations, drug resistance and the road to a cure of chronic myeloid leukemia Thomas O'Hare, Christopher A. Eide, and Michael WN Deininger* Howard Hughes Medical Institute, Oregon Health & Science University, Portland, Oregon, United States OHSU Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States * Corresponding author; email: deininge{at}ohsu.edu. Mutations in the kinase domain (KD) of Bcr-Abl are the most prevalent mechanism of acquired imatinib resistance in patients with chronic myeloid leukemia (CML). Here we examine predisposing factors underlying acquisition of KD mutations, evidence for acquisition of mutations prior to and during therapy, and whether the detection of a KD mutation universally implies resistance. We also provide a perspective on how the second-line Abl inhibitors dasatinib and nilotinib are faring in the treatment of imatinib-resistant CML, especially in relation to specific KD mutations. We discuss the growing importance of the multi-inhibitor-resistant T315I mutant and the therapeutic potential that a T315I inhibitor would have. Lastly, we assess the potential of Abl kinase inhibitor combinations to induce stable responses even in advanced CML and interpret the emerging data in the context of CML pathogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. K. Kenealy, C. B. Christenson, and C. B. Williams Current Therapies for Chronic Myeloid Leukemia Journal of Pharmacy Practice, April 1, 2008; 21(2): 116 - 125. [Abstract] [PDF] J. S. Khorashad, D. Milojkovic, P. Mehta, M. Anand, S. Ghorashian, A. G. Reid, V. De Melo, A. Babb, H. de Lavallade, E. Olavarria, et al. In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib Blood, February 15, 2008; 111(4): 2378 - 2381. [Abstract] [Full Text] [PDF] M. Baccarani, F. Pane, and G. Saglio Monitoring treatment of chronic myeloid leukemia Haematologica, February 1, 2008; 93(2): 161 - 169. [Full Text] [PDF] T. Ernst, P. Erben, M. C. Muller, P. Paschka, T. Schenk, J. Hoffmann, S. Kreil, P. La Rosee, R. Hehlmann, and A. Hochhaus Dynamics of BCR-ABL mutated clones prior to hematologic or cytogenetic resistance to imatinib Haematologica, February 1, 2008; 93(2): 186 - 192. [Abstract] [Full Text] [PDF] G. Saglio, F. Pane, and G. Martinelli State-of-the-art Monitoring for Patients with Chronic Myeloid Leukemia ASCO Educational Book, January 1, 2008; 2008(1): 313 - 317. [Abstract] [Full Text] [PDF] M. W.N. Deininger Imatinib Resistance and the Difficulty of Eradicating Leukemia Stem Cells ASCO Educational Book, January 1, 2008; 2008(1): 318 - 323. [Abstract] [Full Text] [PDF] J. M. Goldman How I treat chronic myeloid leukemia in the imatinib era Blood, October 15, 2007; 110(8): 2828 - 2837. [Abstract] [Full Text] [PDF] R. T. Williams, W. den Besten, and C. J. Sherr Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia Genes & Dev., September 15, 2007; 21(18): 2283 - 2287. [Abstract] [Full Text] [PDF]

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