title: Antagonistic effects of c-myc and Epstein-Barr virus latent genes on the phenotype of human B cells.
abstract: Epstein-Barr virus (EBV) immortalized cells and Burkitt lymphoma cells have a completely different growth pattern and phenotype. EBV immortalized cells express a set of 11 viral genes to accommodate B cell activation and proliferation, whereas EBV-positive Burkitt lymphoma cells highly express the c-myc oncogene that is activated through translocation into 1 of the immunoglobulin loci and EBNA1 as the only viral protein. We have developed a primary human B cell line conditionally immortalized by Epstein-Barr virus in which the viral gene program responsible for the induction of proliferation can be switched on and off by the addition or withdrawal of estrogen (cell line EREB2-5). Starting from this cell line we have generated 2 daughter cell lines that proliferate in a c-myc dependent fashion, 1 with a highly active exogenous c-myc gene (cell line A1) and 1 with a regulatable c-myc gene that can be switched on by withdrawal and switched off by addition of tetracycline (cell line P493-6). The comparison of the 3 cell lines has allowed us to dissect the contribution of c-myc and EBV genes to the regulation of the growth pattern and expression of cell surface molecules. We show that MYC and EBNA2 (and their respective target genes) have opposing effects on the expression of several surface markers involved in B cell activation. We show that MYC contributes to the phenotype of Burkitt lymphoma cells by upregulating CD10 and CD38 and downregulating activation markers. The phenotype of the cells is determined on one hand by the absence of the viral gene products EBNA2 and LMP1 that mediate the phenotype of activated lymphoblasts and to a lesser extent by an active contribution of the c-myc gene.
authors.affiliation: Institut für Klinische Molekularbiologie und Tumorgenetik, Hämatologikum der GSF, München, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Pajic
authors.forename: M S
authors.initials: MS
authors.lastname: Staege
authors.forename: D
authors.initials: D
authors.lastname: Dudziak
authors.forename: M
authors.initials: M
authors.lastname: Schuhmacher
authors.forename: D
authors.initials: D
authors.lastname: Spitkovsky
authors.forename: G
authors.initials: G
authors.lastname: Eissner
authors.forename: M
authors.initials: M
authors.lastname: Brielmeier
authors.forename: A
authors.initials: A
authors.lastname: Polack
authors.forename: G W
authors.initials: GW
authors.lastname: Bornkamm
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D009244:NAD+ Nucleosidase / Q000378:metabolism; D015260:Neprilysin / Q000378:metabolism; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics; D014764:Viral Proteins
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; C402641:EBNA-2 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D008562:Membrane Glycoproteins; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D015260:Neprilysin; D013752:Tetracycline