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

Shyamesh Kumar, Dusan Kunec, Joram J. Buza, Hsin I. Chiang, Huaijun Zhou, Sugalesini Subramaniam, Ken Pendarvis, Hans H. Cheng, Shane C. Burgess

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Background: Marek'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 (CD30 hi) and are in minority, while the non-neoplastic cells (CD30 lo) form the majority of population. MD is a unique natural in-vivo model of human CD30 hi lymphomas with both natural CD30 hi lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30 lo expressing phenotype to CD30 hi expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30 lo and CD30 hi 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.Results: Our results show that a) CD30 lo 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.Conclusions: In the context of the MD lymphoma microenvironment (and potentially in other CD30 hi 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.

Original languageEnglish (US)
Article number123
JournalBMC Systems Biology
Volume6
DOIs
StatePublished - Sep 14 2012

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Keywords

  • CD30
  • Genetic resistance
  • Lymphomas
  • Marek's disease
  • Meq
  • NF-κB
  • Proteomics

ASJC Scopus subject areas

  • Structural Biology
  • Modeling and Simulation
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics

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