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Blood, 1 August 2006, Vol. 108, No. 3, pp. 1065-1072. Prepublished online as a Blood First Edition Paper on April 4, 2006; DOI 10.1182/blood-2005-06-2433. This Article Full Text (PDF) All Versions of this Article: 2005-06-2433v1 108/3/1065    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 Gabillot-Carre, M. Articles by Hermine, O. Search for Related Content PubMed PubMed Citation Articles by Gabillot-Carre, M. Articles by Hermine, O. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 20, 2005 Accepted March 23, 2006 Rapamycin inhibits growth and survival of D-816-V-mutated c-kit mast cells Marion Gabillot-Carre, Yves Lepelletier, Martine Humbert, Paulo de Sepuvelda, Nadine Ben Hamouda, Jean-Pierre Zappulla, Roland Liblau, Antoine Ribadeau-Dumas, Francois Machavoine, Sebastien Letard, Cedric Baude, Aurelie Hermant, Ying Yang, Jacques Vargaftig, Christine Bodemer, Emmanuel Morelon, Olivier Lortholary, Christian Recher, Guy Laurent, Michel Dy, Michel Arock, Patrice Dubreuil, and Olivier Hermine* Centre National de Recherche Scientifique (CNRS) UMR 8147, Hopital Necker; Universite Paris V, Assistance Publique-Hopitaux de Paris, Paris, France Laboratoire AB Science - Institut National de la Sante et de la Recherche Medicale INSERM U604, Marseille, France INSERM UMR599, Centre de Recherche en Cancerologie de Marseille, Laboratoire d'Hematopoiese Moleculaire et Fonctionnelle, Marseille, France Laboratoire d'Immunologie, CHU Purpan, Institut National de la Sante et de la Recherche Medicale (INSERM) U563, Toulouse, France Centre National de Recherche Scientifique (CNRS) UMR 8147, Hopital Necker; Universite Paris V, Assistance Publique-Hopitaux de Paris, Paris, France; Laboratoire AB Science - Institut National de la Sante et de la Recherche Medicale INSERM U604, Marseille, France Service d'Hematologie Adulte, Hopital Necker, Paris, France Service de Dermatologie, Hopital Necker, Paris, France Service de Transplantion Renale et Institut National de la Sante et de la Recherche Medicale (INSERM) U580, Hopital Necker; Universite Paris V, Paris, France Service des Maladies Infectieuses, Hopital Necker, Paris, France Service d'Hemathologie, CHU Purpan, Toulouse, France Centre National de Recherche Scientifique (CNRS) UMR 8147, Hopital Necker; Universite Paris V, Assistance Publique-Hopitaux de Paris, Paris, France; Service d'Hematologie Adulte, Hopital Necker, Paris, France * Corresponding author; email: hermine{at}necker.fr. Two classes of oncogenic mutations of the c-kit tyrosine kinase have been described: the juxtamembrane domain V-560-G-mutation that is preferentially found in gastrointestinal stromal tumors (GISTs), and the kinase domain D-816-V-mutation that is highly representative of systemic mastocytosis (SM). Here, we show that both mutations constitutively activate the mTOR signaling pathway. Surprisingly, the mTOR inhibitor Rapamycin induces only apoptosis in HMC1 cells bearing the D-816-V but not the V-560-G mutation. In support of this unexpected selectivity, Rapamycin inhibits the phosphorylation of 4E-BP1, a downstream substrate of the mTOR pathway, but only in D-816-V HMC1 cells. Importantly, D-816-V mast cells isolated from SM patients or from transgenic mice are sensitive to Rapamycin whereas normal human or mouse mast cells are not. Thus, Rapamycin inhibition appears specific to the D-816-V mutation. At present there is no effective cure for SM patients with the D-816-V mutation. The data presented here provide a rationale to test whether Rapamycin could be a possible treatment for SM and other hematological malignancies with the D-816-V mutation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M.-S. Kim, H. S. Kuehn, D. D. Metcalfe, and A. M. Gilfillan Activation and Function of the mTORC1 Pathway in Mast Cells J. Immunol., April 1, 2008; 180(7): 4586 - 4595. [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] V. Munugalavadla, E. C. Sims, J. Borneo, R. J. Chan, and R. Kapur Genetic and pharmacologic evidence implicating the p85{alpha}, but not p85{beta}, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis Blood, September 1, 2007; 110(5): 1612 - 1620. [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]

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