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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Burkitt Lymphoma / genetics
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Burkitt Lymphoma / metabolism
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Burkitt Lymphoma / virology
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Cell Line, Tumor
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DNA, Neoplasm / genetics
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DNA-Binding Proteins / genetics*
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Down-Regulation
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Epstein-Barr Virus Nuclear Antigens / genetics
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Epstein-Barr Virus Nuclear Antigens / metabolism*
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Gene Expression
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Genes, Viral
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Germinal Center / metabolism
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Germinal Center / virology
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HLA-DR Antigens / metabolism
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Herpesvirus 4, Human / genetics*
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Herpesvirus 4, Human / pathogenicity*
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Humans
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Immunoglobulin M / metabolism
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism
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Lymphoma, B-Cell / virology
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Lymphoma, Large B-Cell, Diffuse / virology
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Lymphoma, Non-Hodgkin / genetics*
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Lymphoma, Non-Hodgkin / metabolism*
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Lymphoma, Non-Hodgkin / virology
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Models, Biological
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Phenotype
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins c-bcl-6
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Transfection
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Viral Matrix Proteins / genetics
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Viral Matrix Proteins / metabolism
Substances
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BCL6 protein, human
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DNA, Neoplasm
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DNA-Binding Proteins
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EBV-associated membrane antigen, Epstein-Barr virus
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Epstein-Barr Virus Nuclear Antigens
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HLA-DR Antigens
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Immunoglobulin M
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-6
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TCL1A protein, human
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Viral Matrix Proteins
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secretory IgM