Researchers develop mouse model of neurofibromatosis

December 09, 1999

DALLAS - December 10, 1999 - Researchers at UT Southwestern Medical Center at Dallas have developed a mouse tumor model for the most common genetic disorder in humans, von Recklinghausen disease, or neurofibromatosis type 1 (NF-1). With the aid of this model, investigators have learned more about why and how patients with NF-1 develop malignant tumors.

Four of every 10,000 babies born have NF-1. These patients, who have one altered and one normal copy of the NF-1 gene, can display a variety of symptoms. Most frequent are the appearance of pigmented skin "café-au-lait" spots and benign tumors of various sizes along their peripheral nerves. These individuals have an increased risk of developing malignancies and can have learning disabilities.

Dr. Luis F. Parada, director of UT Southwestern's Center for Developmental Biology, and colleagues describe in today's issue of Science how various genes interact to activate malignant tumor development. Their mouse model affords a powerful way to devise and test strategies to inhibit tumor growth in neurofibromatosis.

"Although we have known for some time that mutation of the NF-1 gene is the requisite event for the disease to develop, we have also suspected for some time that additional genetic lesions likely take place in the benign tumor cells (the neurofibromas) to convert these cells to malignancy (neurofibrosarcomas)," said Parada. "We believed that the product of NF-1, a tumor suppressor gene, might cooperate with the product of another tumor-suppressor gene, p53, that is located on the same chromosome and in the same region as NF-1 in both man (chromosome 17) and mice (chromosome 11), and is mutated in a majority of malignant tumors."

Parada and colleagues designed their mouse model to see if mutations in NF-1 work cooperatively with mutations in p53 to accelerate malignant tumor formation. Mice with a mutation in one of their two normal p53 gene copies primarily develop tumors of the lymph system and bone. The authors found that the addition of an NF-1 mutation dramatically alters the outcome. Mice with mutations in both genes become ill much more rapidly. And rather than lymphomas and bone tumors, they develop neurofibrosarcomas, tumors with all the traits of malignancies found in human NF-1 patients.

The scientists analyzed tumors from the mice to see if loss of the normal copies of both NF-1 and p53 could be the cause of the increased rate of tumor formation. As with human patients, the malignant tissues had complete loss of the normal copies of both genes.

"We are excited about the fact that we now know which type of genetic lesions must occur in NF-1 patients for malignancies to develop," said Parada, who also directs the Kent Waldrep Foundation Center for Basic Neuroscience Research. "We now can focus on directed therapies to reverse the action of the NF-1 and p53 genes in these tumors."

Other UT Southwestern investigators participating in this study were former postdoctoral fellow Dr. Kristine Vogel; Laura Klesse, a student in the medical scientist training program; postdoctoral fellow Dr. Susana Velasco-Miguel, research scientist Kimberly Meyers and other members of the Center for Developmental Biology; and Dr. Elisabeth Rushing, associate professor of pathology.

Grants from the National Institutes of Health, the National Neurofibromatosis Foundation and the Cancer Association of Greater New Orleans supported the research.
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UT Southwestern Medical Center

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