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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.

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NEOPLASIA

Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells

Marion Gabillot-Carré, Yves Lepelletier, Martine Humbert, Paulo de Sepuvelda, Nadine Ben Hamouda, Jean Pierre Zappulla, Roland Liblau, Antoine Ribadeau-Dumas, François Machavoine, Sébastien Letard, Cédric Baude, Aurélie Hermant, Ying Yang, Jacques Vargaftig, Christine Bodemer, Emmanuel Morelon, Olivier Lortholary, Christian Recher, Guy Laurent, Michel Dy, Michel Arock, Patrice Dubreuil, and Olivier Hermine

From the Centre National de Recherche Scientifique (CNRS) UMR 8147, Hôpital Necker, Paris, France; Université Paris V, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Laboratoire AB Science–Institut National de la Santé et de la Recherche Médicale INSERM U604, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U563, Laboratoire d'Immunologie, CHU Purpan, Toulouse, France; INSERM UMR599, Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Hématopoïèse Moléculaire et Fonctionnelle, Marseille, France; Service d'Hématologie Adulte, Hôpital Necker, Paris, France; Service de Dermatologie, Hôpital Necker, Paris, France; Service de Transplantation Rénale et Institut National de la Santé et de la Recherche Médicale (INSERM) U580, Hôpital Necker, Paris, France; Université Paris V, Paris, France; Service des Maladies Infectieuses, Hôpital Necker, Paris, France; Service d'Hémathologie, CHU Purpan, Toulouse, France.

Two classes of oncogenic mutations of the c-kit tyrosine kinase have been described: the juxtamembrane domain V560G mutation, which is preferentially found in gastrointestinal stromal tumors (GISTs), and the kinase domain D816V mutation, which is highly representative of systemic mastocytosis (SM). Here we show that both mutations constitutively activate the mammalian target of rapamycin (mTOR) signaling pathway. Surprisingly, the mTOR inhibitor rapamycin induces only apoptosis in HMC-1 cells bearing the D816V but not the V560G mutation. In support of this unexpected selectivity, rapamycin inhibits the phosphorylation of 4E-BP1, a downstream substrate of the mTOR pathway, but only in D816V HMC-1 cells. Importantly, D816V 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 D816V mutation. At present there is no effective cure for SM patients with the D816V mutation. The data presented here provide a rationale to test whether rapamycin could be a possible treatment for SM and other hematologic malignancies with the D816V mutation.


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