c-MYC impairs immunogenicity of human B cells.
Deregulation of c-myc expression through chromosomal translocation is essential in the pathogenesis of Burkitt's lymphoma (BL). A characteristic feature of BL cells, compared to Epstein-Barr Virus (EBV)-immortalized B cells, is their lack of immunogenicity. To study the contribution of EBV genes and of the c-MYC protein to this phenotype, we have generated a conditional B cell system in which the viral proliferation program and expression of c-myc can be regulated independently of each other. In cells proliferating due to exogenous c-myc overexpression, the cell surface phenotype, the pattern of proliferation in single cell suspension, and the immunological characteristics of BL cells could be completely recapitulated. Yet, it had remained open whether nonimmunogenicity is the default phenotype when EBNA2 and LMP1 are switched off, or whether c-MYC actively contributes to immunosuppression. We provide evidence also for the latter by showing that c-MYC down-regulates genes of the NF-kappaB and interferon pathway in a dose-dependent fashion. c-MYC acts at at least two different levels, the level of interferon induction as well as at the level of action of type I and type II interferons on their respective target promoters. c-MYC does not block the interferon pathway completely, it shifts the balance and increases the threshold of interferon induction and action.
Schlee
Martin
M
Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, D-81377 München, Germany.
Schuhmacher
Marino
M
Hölzel
Michael
M
Laux
Gerhard
G
Bornkamm
Georg W
GW
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002461:Cell Line, Transformed; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005803:Genes, Immunoglobulin; D016259:Genes, myc; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007372:Interferons / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008211:Lymphocyte Cooperation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014178:Translocation, Genetic; D019139:Tumor Escape / Q000235:genetics* / Q000276:immunology; D014764:Viral Proteins / Q000502:physiology
D016328:NF-kappa B; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D014764:Viral Proteins; D007372:Interferons