Three lines of transgenic mice expressing the tax1 gene of human T-cell leukemia virus, type 1 (HTLV-I) develop peripheral neurofibromas and exocrinopathy of the salivary and lacrimal glands. Further characterization of these transgenic animals has revealed that these mice develop tumors of the adrenal medulla, ciliary body and iris. These observations further strengthen the importance of this transgenic system as a model for human neurofibromatosis in which patients develop similar lesions. HTLV-I is thought to lead to adult T-cell leukemia (ATL) by trans-activation of cellular genes which regulate cellular growth. In vivo studies in these transgenic animals have demonstrated that tax1 activates interleukin 2-receptor as well as granulocyte-macrophage colony stimulating factor (GM-CSF) leading to profound systemic effects. Neurofibromas and salivary epithelial cells from these animals have been shown to secrete large quantities of interleukin 6 (IL-6) which presumably accounts for significant, localized lymphadenopathy composed primarily of B-cells. Tax1 activation of IL-6 is being characterized on a molecular level. HTLV-l has been etiologically linked to HTLV-I-associated myelopathy/tropical spastic paraparesis. However, no understanding of the mechanisms leading to this neuropathology has yet emerged. Neurofibromas from the transgenic mice secrete significant quantities of nerve growth factor (NGF). This observation suggests that tax1 may stimulate NGF production and may provide important new insights into the mechanism of HTLV-I-induced neurologic disease. A tax1-responsive element in the NGF promoter has been identified which stimulates NGF production by 20-fold. This result suggests that neurologic disease may result from HTLV-I expression in perineural cells which cause perturbated secretion of factors which may lead to neurologic dysfunction. Nerve growth factor receptor is also produced in the tumors. Thus, an autocrine mechanism of transformation may result in the formation of neurofibromas in these mice.
