EBNA2 interferes with the germinal center phenotype by downregulating BCL6 and TCL1 in non-Hodgkin's lymphoma cells.
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.
Boccellato
Francesco
F
Istituto Pasteur-Fondazione Cenci-Bolognetti, Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy.
Anastasiadou
Eleni
E
Rosato
Paola
P
Kempkes
Bettina
B
Frati
Luigi
L
Faggioni
Alberto
A
Trivedi
Pankaj
P
D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005814:Genes, Viral; D018858:Germinal Center / Q000378:metabolism / Q000821:virology; D006684:HLA-DR Antigens / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000472:pathogenicity*; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000821:virology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000821:virology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism* / Q000821:virology; D008954:Models, Biological; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D014162:Transfection; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism
C084103:BCL6 protein, human; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D006684:HLA-DR Antigens; D007075:Immunoglobulin M; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C090851:TCL1A protein, human; D014763:Viral Matrix Proteins; C033027:secretory IgM