EXPRESSION OF KIT IN NEUROFIBROMIN-DEFICIENT HUMAN SCHWANN-CELLS - ROLE IN SCHWANN-CELL HYPERPLASIA ASSOCIATED WITH TYPE-1 NEUROFIBROMATOSIS

Type 1 Neurofibromatosis (NF1) is characterized by the formation of ne urofibromas, benign tumors composed mainly of Schwann cells, which can turn malignant to form neurofibrosarcomas. Neurofibromin, the protein product of the Nf1 gene, is believed to act as a tumor suppressor, ac celerating the conversion of the oncogene Ras to its inactive form. Th e absence of neurofibromin could therefore lead to higher Ras activity in Schwann cells, resulting in uncontrolled growth through a cascade of events not yet elucidated. We describe the abnormal expression of h igh levels of the Kit tyrosine kinase receptor in both NF1-derived Sch wann cell lines and tissue, as compared to primary Schwann cells or sc hwannoma-derived cells. High levels of Kit expression in the neurofibr osarcoma-derived Schwann cells correlate with a decrease in neurofibro min expression. Using inhibitors of tyrosine kinase receptors, we foun d that proliferation of the neurofibrosarcoma-derived cells is depende nt: upon activation of a subclass of tyrosine-kinase receptors. The pr oliferation of these cells is not dependent upon an autocrine loop inv olving typical Schwann cell mitogens. Finally, the proliferation of th e neurofibrosarcoma-derived Schwann cells can be increased by stimulat ion with Kit ligand. These data implicate Kit as one of the components leading to the Schwann cell hyperplasia observed in NF1.