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Logo of bmcsysbioBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Systems Biology
 
BMC Syst Biol. 2012; 6: 123.
Published online Sep 14, 2012. doi:  10.1186/1752-0509-6-123
PMCID: PMC3472249
Nuclear Factor kappa B is central to Marek’s Disease herpesvirus induced neoplastic transformation of CD30 expressing lymphocytes in-vivo
Shyamesh Kumar,corresponding author#1 Dusan Kunec,#2 Joram J Buza,3 Hsin-I Chiang,4 Huaijun Zhou,5 Sugalesini Subramaniam,6 Ken Pendarvis,7 Hans H Cheng,8 and Shane C Burgesscorresponding author7,8
1Department of Pathobiology and Population Medicine, Mississippi State University, PO Box 6100, MS, Mississippi State, 39762, USA
2Institut für Virologie, Freie Universität Berlin, Berlin, Germany
3School of Life Sciences and Bioengineering, Nelson Mandela African Institute of Science and Technology, PO Box 447, Arusha, Tanzania
4Department of Bioengineering, University of California-San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA
5Department of Poultry Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, 77843, USA
6Comparative Medicine and Integrative Biology Graduate Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI, 48824, USA
7College of Agriculture and Life Sciences, University of Arizona, P.O. Box 210036, Tucson, AZ, 85721, USA
8USDA-ARS, Avian Disease and Oncology Laboratory, 4279 East Mount Hope Road, East Lansing, MI, 48823, USA
corresponding authorCorresponding author.
#Contributed equally.
Shyamesh Kumar: skumar/at/cvm.msstate.edu; Dusan Kunec: dusan.kunec/at/fu-berlin.de; Joram J Buza: joram.buza/at/nm-aist.ac.tz; Hsin-I Chiang: hchiang/at/eng.ucsd.edu; Huaijun Zhou: hzhou/at/poultry.tamu.edu; Sugalesini Subramaniam: subram28/at/cvm.msu.edu; Ken Pendarvis: jkpendarvis/at/email.arizona.edu; Hans H Cheng: hcheng/at/msu.edu; Shane C Burgess: sburgess/at/cals.arizona.edu
Received June 13, 2012; Accepted September 4, 2012.
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 (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.
Results
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.
Conclusions
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.
Keywords: Marek’s disease, Lymphomas, Meq, NF-κB, Genetic resistance, CD30, Proteomics
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