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This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sawyers, C. L. Search for Related Content PubMed Articles by Sawyers, C. L. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 July 2003, Vol. 102, No. 1, pp. 4-5 Resistance to imatinib: more and more mutations In the short time since the introduction of imatinib in 2001, investigators have already defined the primary mechanisms of drug resistance: mutations in the BCR-ABL gene that affect drug binding or an overall increase in the level of BCR-ABL protein due to gene amplification. In this issue, Branford and colleagues (page 276) report the first comprehensive mutation analysis of an unselected population of chronic myeloid leukemia (CML) patients treated with imatinib. The key finding is a very tight correlation between detection of a mutation and relapse, dispelling any remaining doubt about the causal role that mutations play in imatinib resistance. A few additional points are worth noting. First, the authors find that mutations in the adenosine triphosphate (ATP)—binding loop confer a worse prognosis than other mutations, raising the possibility that early detection would mandate a change in treatment. Second, new clinical mutations are described here that were also picked up in a cleverly designed in vitro screen for imatinib resistance (Azam et al, Cell. 2003;112:831-843). Finally, the probability for finding a mutation increases with disease duration. This last point is particularly important because it provides the first epidemiologic support for a clonal expansion model of imatinib resistance arising from pre-existing mutant subclones (Shah et al, Cancer Cell. 2002;2:117-125). The theory goes as follows. The CML clone makes sequence errors during DNA replication, some of which affect BCR-ABL. Over time, increasing clonal diversity raises the likelihood of generating imatinib-resistant subclones that expand in the setting of imatinib treatment. This model is based on data from patients who were treated with imatinib several years after their initial CML diagnosis. Will early imatinib treatment of newly diagnosed CML patients prevent this clonal evolution? Or is it too late? Time will tell. Charles L. Sawyers University of California Los Angeles CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis Susan Branford, Zbigniew Rudzki, Sonya Walsh, Ian Parkinson, Andrew Grigg, Jeff Szer, Kerry Taylor, Richard Herrmann, John F. Seymour, Chris Arthur, David Joske, Kevin Lynch, and Tim Hughes Blood 2003 102: 276-283. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sawyers, C. L. Search for Related Content PubMed Articles by Sawyers, C. L. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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