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Blood, 1 February 2004, Vol. 103, No. 3, pp. 1078-1084. Prepublished online as a Blood First Edition Paper on October 9, 2003; DOI 10.1182/blood-2003-07-2477. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2477v1 103/3/1078    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 Fumo, G. Articles by Neckers, L. Search for Related Content PubMed PubMed Citation Articles by Fumo, G. Articles by Neckers, L. Related Collections Neoplasia Apoptosis Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells Gerard Fumo, Cem Akin, Dean D. Metcalfe, and Len Neckers From the Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, MD; and Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. Mutations in the proto-oncogene c-kit cause constitutive kinase activity of its product, KIT protein, and are associated with human mastocytosis and gastrointestinal stromal tumors (GISTs). Although currently available tyrosine kinase inhibitors are effective in the treatment of GISTs, there has been limited success in the treatment of mastocytosis. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinoid ansamycin antibiotic, which binds to heat shock protein 90 (hsp90) causes destabilization of various hsp90-dependent kinases important in oncogenesis. Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure. These data were validated using Cos-7 cells transfected with wild-type and mutated KIT. 17-AAG promotes cell death of both HMC mast cell lines. In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction. These data provide compelling evidence that 17-AAG may be effective in the treatment of c-kit-related diseases including mastocytosis, GISTs, mast cell leukemia, subtypes of acute myelogenous leukemia, and testicular cancer. (Blood. 2004;103:1078-1084) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Babchia, A. Calipel, F. Mouriaux, A.-M. Faussat, and F. Mascarelli 17-AAG and 17-DMAG-Induced Inhibition of Cell Proliferation through B-Raf Downregulation in WTB-Raf-Expressing Uveal Melanoma Cell Lines Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2348 - 2356. [Abstract] [Full Text] [PDF] A. Tefferi, S. Verstovsek, and A. Pardanani How we diagnose and treat WHO-defined systemic mastocytosis in adults Haematologica, January 1, 2008; 93(1): 6 - 9. [Full Text] [PDF] E. Voisset, S. Lopez, P. Dubreuil, and P. De Sepulveda The tyrosine kinase FES is an essential effector of KITD816V proliferation signal Blood, October 1, 2007; 110(7): 2593 - 2599. [Abstract] [Full Text] [PDF] R. Kondo, K. V. Gleixner, M. Mayerhofer, A. Vales, A. Gruze, P. Samorapoompichit, K. Greish, M.-T. Krauth, K. J. Aichberger, W. F. Pickl, et al. Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells Blood, July 15, 2007; 110(2): 661 - 669. [Abstract] [Full Text] [PDF] J. Bae, C. Mitsiades, Y.-T. Tai, R. Bertheau, M. Shammas, R. B. Batchu, C. Li, L. Catley, R. Prabhala, K. C. Anderson, et al. Phenotypic and Functional Effects of Heat Shock Protein 90 Inhibition on Dendritic Cell J. Immunol., June 15, 2007; 178(12): 7730 - 7737. [Abstract] [Full Text] [PDF] J. Pan, A. 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Cardiothorac. Surg., October 1, 2005; 28(4): 617 - 621. [Abstract] [Full Text] [PDF] R. A. Mesa, D. Loegering, H. L. Powell, K. Flatten, S. J. H. Arlander, N. T. Dai, M. P. Heldebrant, B. T. Vroman, B. D. Smith, J. E. Karp, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine Blood, July 1, 2005; 106(1): 318 - 327. [Abstract] [Full Text] [PDF] A. Sonnenblick, C. Levy, and E. Razin Interplay between MITF, PIAS3, and STAT3 in Mast Cells and Melanocytes Mol. Cell. Biol., December 15, 2004; 24(24): 10584 - 10592. [Abstract] [Full Text] [PDF]

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