Lethal Cutaneous Disease in Transgenic Mice Conditionally Expressing Type I Human T Cell Leukemia Virus Tax

摘要: Abstract Type I human T cell leukemia virus (HTLV-I) is etiologically linked with adult leukemia, an aggressive and usually fatal expansion of activated CD4+ lymphocytes that frequently traffic to skin. transformation induced by HTLV-I involves the action 40-kDa viral Tax transactivator protein. both stimulates long terminal repeat deregulates expression select cellular genes altering activity specific host transcription factors, including cyclic AMP-responsive element-binding protein (CREB)/activating factor, NF-κB/Rel, serum response factor. To study initiating events involved in Tax-induced transformation, we generated “Tet-off” transgenic mice conditionally expressing a lymphocyte-restricted manner (EμSRα promoter-enhancer) either wild-type or mutant forms selectively compromise NF-κB (M22) CREB/activating factor (M47) activation pathways. Wild-type M47 Tax-expressing mice, but not M22-Tax developed progressive alopecia, hyperkeratosis, skin lesions containing profuse CD4 infiltrates evidence deregulated inflammatory cytokine production. In addition, these animals displayed systemic lymphadenopathy splenomegaly. These findings suggest Tax-mediated plays key role development this disease shares several features common occurring during preleukemic stage HTLV-I-infected patients. Of note, completely resolved when transgene was suppressed administration doxycycline, emphasizing played oncoprotein observed pathology.