Nuclear Factor Kappa B is central to Marek’s Disease lymphomagenesis

Chicken Marek’s disease (MD) is a unique naturally occurring model for human herpesvirus-induced lymphomas that over-express the “Hodgkin’s disease antigen” (TNFRSF-8; CD30) on the lymphoma’s neoplastically-transformed cells. We used transcriptomics, proteomics, computational systems biology and reductionist molecular biology to identify the differences between the CD30(hi) lymphoma cells and the non-transformed CD30(lo) MD lymphoma cells. We propose specific mechanisms of neoplastic transformation, genetic resistance to lymphomagenesis and impact of lymphoma microenvironment on CD30(hi) cell development. We demonstrate that: a) in situ, CD30(lo) cells are pre-neoplastic and we identify the proteome involved in transformation as well as potential mechanisms that may be controlled by MDV oncogene Meq; b) MD herpesvirus, (via its Meq oncogene) can drive a feed forward loop that induces CD30 transcription and overexpression, increased CD30 signaling, which then activates NFκB and, in turn, increases Meq transcription; c) Meq transcriptional repression or activation from the CD30 promoter generally correlates with a polymorphism in the CD30 promoter between MD-resistant and -susceptible chicken genotypes and so a herpesvirus has evolved to utilize NFκB as a direct transcriptional activator for its oncogene. A dual color, balanced design was carried on eight sorted lymphoma cells from white leghorn chickens infected with MDV GA/22 strain. Each of two sample types, CD30(hi) and CD30(lo) cells, includes four biological replicates for total RNA extraction and labeling. A Dye swap was used in four biological repeats of CD30(hi) to CD30(lo) cells comparison. Background subtracted signal intensities were collected from 4 arrays and normalized for data analysis.