Nuclear Factor kappa B is central to Marek’s Disease herpesvirus induced neoplastic transformation of CD30 expressing lymphocytes in-vivo

Our results show that a) CD30lo lymphocytes are pre-neoplastic precursors and not merely reactive lymphocytes; b) multiple transformation mechanisms exist and are potentially controlled by Meq; c) Meq can drive a feed-forward cycle that induces CD30 transcription, increases CD30 signaling which activates NF-κB, and, in turn, increases Meq transcription; d) Meq transcriptional repression or activation of the CD30 promoter generally correlates with polymorphisms in the CD30 promoter distinguishing MD-lymphoma resistant and susceptible chicken genotypes e) MDV oncoprotein Meq interacts with proteins involved in physiological processes central to lymphomagenesis.In the context of the MD lymphoma microenvironment (and potentially in other CD30hi lymphomas as well), our results show that the neoplastic transformation is a continuum and the non-neoplastic cells are actually pre-neoplastic precursor cells and not merely immune bystanders. We also show that NF-κB is a central player in MDV induced neoplastic transformation of CD30-expressing lymphocytes in vivo. Our results provide insights into molecular mechanisms of neoplastic transformation in MD specifically and also herpesvirus induced lymphoma in general.Lymphomas are the 6th leading cause of cancer mortality in the USA especially in patients younger than 40？years [1,2]. More than 11% of human lymphomas overexpress the CD30 antigen (a.k.a. Hodgkin’s Disease antigen, or Tumor Necrosis Factor Receptor Superfamily Member 8 [TNFRSF8])—this includes all Hodgkin’s lymphomas (HL) and some non-Hodgkin’s lymphomas (NHL); e.g. anaplastic large cell lymphoma (ALCL), primary cutaneous anaplastic large cell lymphoma (PCTL), adult T-cell leukemia/lymphoma (ATLL), peripheral T-cell lymphoma (PTCL), natural killer (NK)/T-cell lymphoma, nasal and enteropathy type T cell lymphoma [3-5]. Natural “spontaneous” animal models that mimic the human lymphoma microenvironment, and have a functional immune system, are invaluable tools to unders