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Blood, 15 July 2005, Vol. 106, No. 2, pp. 721-724. Prepublished online as a Blood First Edition Paper on March 24, 2005; DOI 10.1182/blood-2004-12-4617. This Article Full Text (PDF) All Versions of this Article: 2004-12-4617v1 106/2/721    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 Growney, J. D Articles by Gilliland, D G Search for Related Content PubMed PubMed Citation Articles by Growney, J. D Articles by Gilliland, D G Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 14, 2004 Accepted March 14, 2005 Activation mutations of human c-KIT resistant to imatinib are sensitive to the tyrosine kinase inhibitor PKC412 Joseph D Growney, Jennifer J Clark, Jennifer Adelsperger, Richard Stone, Doriano Fabbro, James D Griffin, and D G Gilliland* Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA Dana-Farber Cancer Institute, Boston, MA, USA Novartis Pharma AG, Basel, Switzerland Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA * Corresponding author; email: ggilliland{at}rics.bwh.harvard.edu. Constitutively activated forms of the trans-membrane receptor tyrosine kinase c-KIT have been associated with systemic mast cell disease, acute myeloid leukemia and gastrointestinal stromal tumors. Reports of the resistance of the kinase domain mutation D816V to the ATP-competitive kinase inhibitor imatinib prompted us to characterize fourteen c-KIT mutations reported in association with human hematologic malignancies for transforming activity in the murine hematopoietic cell line Ba/F3, and for sensitivity to the tyrosine kinase inhibitor PKC412. Ten of fourteen c-KIT mutations conferred IL-3 independent growth. c-KIT D816Y and D816V transformed cells were sensitive to PKC412 despite resistance to imatinib. In these cells, PKC412, but not imatinib, inhibited autophosphorylation of c-KIT and activation of downstream effectors Stat5 and Stat3. Variable sensitivities to PKC412 or imatinib were observed among other mutants. 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