Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation

Mastocytosis is a rare neoplastic disease characterized by a pathologic accumulation of tissue mast cells (MCs). Mastocytosis is often associated with a somatic point mutation in the Kit protooncogene leading to an Asp/Val substitution at position 816 in the kinase domain of this receptor. The contribution of this mutation to mastocytosis development remains unclear. In addition, the clinical heterogeneity presented by mastocytosis patients carrying the same mutation is unexplained. We report that a disease with striking similarities to human mastocytosis develops spontaneously in transgenic mice expressing the human Asp816Val mutant Kit protooncogene specifically in MCs. This disease is characterized by clinical signs ranging from a localized and indolent MC hyperplasia to an invasive MC tumor. In addition, bone marrow–derived MCs from transgenic animals can be maintained in culture for >24 mo and acquire growth factor independency for proliferation. These results demonstrate a causal link in vivo between the Asp816Val Kit mutation and MC neoplasia and suggest a basis for the clinical heterogeneity of human mastocytosis

Pertussis Toxin Reduces the Number of Splenic Foxp3 + Regulatory T Cells

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

International audienceTwo 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