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

Abstract

BackgroundMarek’s Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2; MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30hi) and are in minority, while the non-neoplastic cells (CD30lo) form the majority of population. MD is a unique natural in-vivo model of human CD30hi lymphomas with both natural CD30hi lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30lo expressing phenotype to CD30hi expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30lo and CD30hi cells to identify key pathways of neoplastic transformation. We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-κB) family and CD30; we also identify a novel Meq protein interactome.ResultsOur 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.ConclusionsIn 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.

Imaging Mass Spectrometry and Proteome Analysis of Marek’s Disease Virus-Induced Tumors

“…Furthermore, two of the downregulated proteins are associated with signaling pathways that regulate the cytoskeleton (FYB [55] and PAK2 [56]). Burgess et al previously demonstrated that Hodgkin’s disease antigen (CD30) is upregulated in tumors induced by HPRS-16 or GA/22 in line 7 2 and 6 1 chickens as well as Ross broilers (57, 58). We did not observe this CD30 upregulation in tumors induced by the very virulent RB-1B strain upon infection of Valo SPF chickens, suggesting that the virus strain and chicken line might influence the upregulation of CD30.…”

Comparison and contrast of genes and biological pathways responding to Marek’s disease virus infection using allele-specific expression and differential expression in broiler and layer chickens

“…It is also interesting to note that growth hormone ( GH ), one of the three MD resistance genes identified [8], also lies at the start of the JAK/STAT pathway though we could not evaluate for ASE due to the lack of SNPs in the F 1 progeny. Interestingly, nuclear factor-kappa B (NF-κ B), which regulates genes associated with cell survival, proliferation, programmed cell death (PCD), stress, inflammation, and immunity was previously shown to be a key component of MDV infection [26] and showed ASE in the layers in this study as well as being a member of the TLR signaling pathway among others (e.g., viral carcinogenesis, B and T cell receptor signaling, chemokine signaling). If the genes at the beginning of the aforementioned pathways do confer genetic resistance to MD, then this has strong implications on how to analyze RNA-Seq data to identify strong candidate genes in other complex traits.…”

Understanding the molecular basis of disease is crucial to improving the design and construction of herpesviral vectors for veterinary vaccines

“…What could be required now is methodologies compile and correlate the massive amount of data that exists for MD, MD viruses and MD vaccines. The recently application of a systems biology approach to MD highlights the extensive and complex interactions between the host and the pathogen [30]. Modelling these interactions in a nonbiased manner could help resolve this continuing problem.…”