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J Virol ; 81(5): 2274-82, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17151114

ABSTRACT

Epstein-Barr virus (EBV)-negative diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma-derived cell lines infected in vitro with a recombinant EBV expressed type II/III latency. High expression of EBNA2 inversely correlated with expression of germinal center (GC)-associated genes, BCL6 and TCL1. The decreased expression of BCL6 appeared to be dose dependent, with almost complete abrogation in highly EBNA2-expressing clones. The role of EBNA2 in negative regulation of these genes was confirmed by transfection and in a hormone-inducible EBNA2 cell system. LMP1 transfection reduced expression of TCL1, but not of BCL6, in DLBCLs. The GC-associated gene repression was at the transcriptional level and CBF1 independent. A decrease in HLA-DR, surface immunoglobulin M, and class II transactivator expression and an increase in CCL3, a BCL6 repression target, was observed in EBNA2-expressing clones. Since BCL6 is indispensable for GC formation and somatic hypermutations (SHM), we suggest that the previously reported lack of SHM seen in EBNA2-expressing GC cells from infectious mononucleosis tonsils could be due to negative regulation of BCL6 by EBNA2. These findings suggest that EBNA2 interferes with the GC phenotype.


Subject(s)
DNA-Binding Proteins/genetics , Epstein-Barr Virus Nuclear Antigens/metabolism , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/pathogenicity , Lymphoma, Non-Hodgkin/genetics , Lymphoma, Non-Hodgkin/metabolism , Proto-Oncogene Proteins/genetics , Base Sequence , Burkitt Lymphoma/genetics , Burkitt Lymphoma/metabolism , Burkitt Lymphoma/virology , Cell Line, Tumor , DNA, Neoplasm/genetics , Down-Regulation , Epstein-Barr Virus Nuclear Antigens/genetics , Gene Expression , Genes, Viral , Germinal Center/metabolism , Germinal Center/virology , HLA-DR Antigens/metabolism , Humans , Immunoglobulin M/metabolism , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/virology , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/virology , Lymphoma, Non-Hodgkin/virology , Models, Biological , Phenotype , Proto-Oncogene Proteins c-bcl-6 , Transfection , Viral Matrix Proteins/genetics , Viral Matrix Proteins/metabolism
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