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Blood, 15 July 2007, Vol. 110, No. 2, pp. 678-685. Prepublished online as a Blood First Edition Paper on March 29, 2007; DOI 10.1182/blood-2006-10-054098. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-054098v1 110/2/678    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Peng, C. Articles by Li, S. Search for Related Content PubMed PubMed Citation Articles by Peng, C. Articles by Li, S. Related Collections Oncogenes and Tumor Suppressors Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I–induced leukemia and suppresses leukemic stem cells Cong Peng1, Julia Brain2, Yiguo Hu1, Ami Goodrich1, Linghong Kong1, David Grayzel2, Roger Pak2, Margaret Read2, and Shaoguang Li1 1 The Jackson Laboratory, Bar Harbor, ME; 2 Infinity Pharmaceuticals, Cambridge, MA Development of kinase domain mutations is a major drug-resistance mechanism for tyrosine kinase inhibitors (TKIs) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome–positive chronic myelogenous leukemia (CML) where all available kinase inhibitors in clinic are ineffective against the BCR-ABL mutant, T315I. As an alternative approach to kinase inhibition, an orally administered heat shock protein 90 (Hsp90) inhibitor, IPI-504, was evaluated in a murine model of CML. Treatment with IPI-504 resulted in BCR-ABL protein degradation, decreased numbers of leukemia stem cells, and prolonged survival of leukemic mice bearing the T315I mutation. Hsp90 inhibition more potently suppressed T315I-expressing leukemia clones relative to the wild-type (WT) clones in mice. Combination treatment with IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both WT and T315I leukemic cells. These results provide a rationale for use of an Hsp90 inhibitor as a first-line treatment in CML by inhibiting leukemia stem cells and preventing the emergence of imatinib-resistant clones in patients. Rather than inhibiting kinase activity, elimination of mutant kinases provides a new therapeutic strategy for treating BCR-ABL–induced leukemia as well as other cancers resistant to treatment with tyrosine kinase inhibitors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. J. Neering, T. Bushnell, S. Sozer, J. Ashton, R. M. Rossi, P.-Y. Wang, D. R. Bell, D. Heinrich, A. Bottaro, and C. T. Jordan Leukemia stem cells in a genetically defined murine model of blast-crisis CML Blood, October 1, 2007; 110(7): 2578 - 2585. [Abstract] [Full Text] [PDF]

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