Abstract
Background: Mastocytosis is a rare and heterogenous disease characterized by abnormal accumulation and activation of mast cells in one or several organs. The clinical spectrum of the pathology varies from relatively mild forms with isolated skin lesions to very aggressive forms with wide systemic involvement, often fatal. The disease can affect both children and adults. While most pediatric forms resolve during or in late puberty, adult cases are persistent and may evolve into aggressive forms. A somatic KIT D816V mutation is detected in 85% of patients but all attempts to demonstrate its oncogenic effect have failed. There is strong evidence that the KIT D816V mutation alone cannot trigger the disease and that other genes may be involved. Aims: The French national reference center of mastocytosis (CEREMAST) has recorded more than 2000 patients with sporadic mastocytosis and 60 familial cases. Since KIT mutations do not fully explain the pathophysiology of the disease, we sought to identify other mutations that could act synergistically with KIT D816V to induce the disease. Methods: We focused on patients presenting with mastocytosis in particular syndromic contexts within the pediatric cohort followed at Necker hospital; we first investigated the molecular mechanisms underlying mastocytosis onset in patients with both congenital mastocytosis and an extremely rare polymalformative syndrome. Results: From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS) and congenital mastocytosis, we could demonstrate the implication of the hedgehog (Hh) pathway in mastocytosis. GCPS is a very rare syndrome resulting from haploinsufficiency of GLI3, the major repressor gene of the hedgehog (Hh) family. We showed that the Hh pathway is barely active in normal primary mast cells (MCs) and overactive in neoplastic MCs. Using a GCPS mouse model, we demonstrated that mutations in GLI3 and KIT have a synergistic, tumorigenic effect leading to mastocytosis onset. We also showed that Hh inhibitors suppress abnormal mast cell proliferation, in vitro, and extend the survival of mice with aggressive systemic mastocytosis (ASM). Summary/Conclusion: Thus, for the first time, we revealed the involvement of Hh signaling pathway in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in ASM. Finally, we provided the first evidence that Hh inhibitors represent a promising new therapeutic target.
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