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Blood, 1 June 2007, Vol. 109, No. 11, pp. 5011-5015. Prepublished online as a Blood First Edition Paper on February 15, 2007; DOI 10.1182/blood-2006-01-015347. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2006-01-015347v1 109/11/5011    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 Ray, A. Articles by Griffin, J. D Search for Related Content PubMed PubMed Citation Articles by Ray, A. Articles by Griffin, J. D Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 12, 2006 Accepted December 13, 2006 Identification of Bcr/Abl point mutations conferring resistance to the Abl kinase inhibitor AMN107 (Nilotinib) by a random mutagenesis study Arghya Ray, Sandra W. Cowan-Jacob, Paul W. Manley, Jurgen Mestan, and James D Griffin* Department of Medical Oncology, Dana-Farber Cancer Institute, Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States Novartis Institutes for Biomedical Research, Basel, Switzerland * Corresponding author; email: james_griffin{at}dfci.harvard.edu. Patients with advanced stages of chronic myeloid leukemia (CML) often manifest imatinib resistance associated with point mutations in Bcr-Abl. AMN107 is a new higher-potency inhibitor of Bcr-Abl. To identify mutations in Bcr/Abl that could result in resistance to AMN107, a cDNA library of BCR-ABL mutants was introduced into Ba/F3 cells followed by selection in AMN107 (0.125-0.5 µM). Eighty six individual, drug-resistant, colonies were recovered and the SH3, SH2, and kinase domains of BCR/ABL were sequenced. Forty six colonies had single point mutations in BCR/ABL, with a total of 17 different mutations, all within the kinase domain. The other 40 colonies had multiple point mutations and were not analyzed further. Each of the 17 single point mutants were reconstructed by site directed mutagenesis of native BCR/ABL and found to be approximately 2.5- to 800-fold more resistant to AMN107 than native Bcr/Abl. The mutations included 6 known imatinib-resistant mutations including T315I, which showed complete resistance to AMN107. Interestingly, the majority of AMN107-resistant mutants were also resistant to imatinib. These results may predict some of the resistance mutations that will be detected in clinical trials with this kinase inhibitor. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Jabbour, D. Jones, H. M. Kantarjian, S. O'Brien, C. Tam, C. Koller, J. A. Burger, G. Borthakur, W. G. Wierda, and J. Cortes Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations Blood, September 3, 2009; 114(10): 2037 - 2043. [Abstract] [Full Text] [PDF] S. Soverini, A. Gnani, S. Colarossi, F. Castagnetti, E. Abruzzese, S. Paolini, S. Merante, E. Orlandi, S. de Matteis, A. Gozzini, et al. 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