NEUROFIBROMATOSIS-1 MUTATIONS AND NEUROBLASTOMA

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Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders of man. Patients with NF1 often develop benign neurofibromas and are at increased risk for several malignant nervous system tumors. The gene responsible for NF1 has recently been cloned and shown to encode a protein that can activate the GTPase of p2lras. We have found that NF1 mutations are frequent in a neural crest derived tumor, neuroblastoma, which is not associated with NF1. The detection of frequent NF1 mutations in neuroblastomas suggests that these mutations contribute to the development of this tumor. NF1 deficient neuroblastomas differ from NF1 tumor cell lines in showing little, if any, increase in ras-GTP levels. To follow up on these findings we propose several experiments. An important question that we will address is whether NF1 is a neuroblastoma tumor suppressor. To determine if NF1 mutations occur in primary neuroblastomas we will test blood and tumor samples from patients with neuroblastoma. To analyze whether the NF1 gene is a neuroblastoma tumor suppressor, we will reestablish expression in the deficient cell lines and test their in vitro and in vivo growth potential. The NF1 deficient cell lines will be used to address two questions. First, we will follow up on our finding that, unlike NF1 malignant tumor cells, NF1 deficient neuroblastomas have only low levels of ras-GTP. Secondly, we will analyze whether any ras-mediated processes are abnormal in NF1 deficient cells. In these experiments we shall analyze ligand stimulated activation of the c-raf-1 and MAP protein kinases, as well as c-fos mRNA induction. We believe that both these approaches have significant potential to help determine the function of NF1, which is the next challenge in this field.