Mareks Disease a CD4 T cell lymphoma of chickens caused by the Gallid herpes virus type 2 is a unique natural ani mal model for herpesvirus induced lymphomagenesis in general and CD30hi lymphomas specifically. CD30 overexpression is an evolutionarily conserved process in neoplastic selleckchem transformation in human and chicken lymphomas of different etiologies. Like human CD30hi lymphomas, MD lymphomas are a het erogeneous mix of a minority of neoplastically trans formed lymphocytes, surrounded by majority of non transformed lymphocytes. Physio logically, CD30 signaling modulates cell survival and death, however, in CD30hi lymphoma cells, it preferen tially promotes cell survival. CD30 overexpres sion induces a T helper 2 or regulatory T cell like cytokine microenvironment, which is antagonistic to cell mediated Inhibitors,Modulators,Libraries immunity, immune evasive, and pro motes lymphomagenesis.
CD30 signaling activates the transcription factor Nu clear Factor kappa B, which regulates genes associated with cell survival, proliferation, programmed cell death, stress and immunity. Constitutive NFB activation, due to CD30 overexpression and lig and dependent independent Inhibitors,Modulators,Libraries signaling, results in neo plastic transformation in human CD30hi lymphomas. The human oncogenic viruses Epstein Barr virus and Kaposis sarcoma associated herpes virus both subvert NFB activation via the CD30 signaling pathway when transforming cells as MDV does in the chicken. This suggests that the CD30 signaling pathway is fundamental, Inhibitors,Modulators,Libraries or at least highly beneficial to herpesvirus survival. MD transformed lymphocytes have increased MDV oncogene Meq expression.
Meq is essential for MDV lymphomagenesis and a positive correl ation exists between Meq and CD30 expression. Also, the chicken CD30 promoter has 15 known Meq binding sites, and Meqs promoter has at least one NFB binding Inhibitors,Modulators,Libraries site. We hypothesize that a feed forward loop exists, with Meq induced CD30 Inhibitors,Modulators,Libraries overexpression, constitutive NFB activation with resulting increased Meq transcriptionfavoring neoplastic sellckchem transformation. Here we show, using MD lymphocytes isolated directly ex vivo that they are either neoplastically transformed and express high levels of CD30 or are non transformed and express low levels of CD30 that, 1 neoplastic transformation is a continuum and the CD30lo lymphocytes within the tumor microenviron ment are pre neoplastic, 2 as the lymphocytes become more neoplastically transformed they become more immune evasive, 3 the MDV oncogene Meq, has a dir ect role in this process and 4 NFB has a central role in this neoplastic transformation.
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