Research Group Prof. Hans Helmut Niller
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Epstein-Barr virus: the first human tumor virus
Epstein-Barr virus (EBV), a gammaherpesvirus infecting humans, has been discovered 50 years ago in cultured cells derived from Burkitt lymphoma (BL), an endemic childhood tumor mainly of equatorial Africa . In addition to BL, EBV plays a role in the initiation and progression of other primarily malignant lymphomas, too, and it is the causative agent of early onset posttransplant lymphoproliferative disorder (PTLD). Due to its association with BL and its astonishing ability to morphologically transform and immortalize B cells to lymphoblastoid cell lines (LCL), EBV was considered a purely lymphotropic virus. Finding viral DNA in cellular DNA from biopsies of anaplastic carcinomas of the nasopharynx (NPC) by DNA hybridization did not change that view, because NPC as a lymphoepithelial tumor contains high numbers of infiltrating lymphocytes . Localizing the virus specifically to the malignant epithelial cells, but not the great many infiltrating lymphocytes, first established EBV infection of non-lymphatic cells and paved the way for the new concept of EBV as an epithelial tumor virus . Subsequently, the association of EBV with gastric carcinomas (EBVaGC) was established, too [4, 5].
Molecular pathogenesis of EBV associated lymphomas
Another conceptual shift was brought about by our discovery of a binding site for the oncoprotein c-Myc in the locus control region of EBV . A fundamental difference between the pathogenesis of LCL-like tumors on one side, and of primarily malignant EBV associated lymphomas on the other side became thereby obvious: Early onset PTLD originate under conditions of severe immune suppression and depend on viral transforming functions, including Epstein-Barr virus nuclear antigens (EBNAs) and latent membrane proteins (LMPs) that are expressed both in PTLDs in vivo and in LCLs immortalized in vitro . On the other hand, BL and Hodgkin lymphoma originate under conditions of hyperstimulation of the lymphoid germinal center reaction, and they do not depend on EBNA2 which most of them do not express [6-8]. The need to counter-balance the pro-apoptotic force of translocated c-Myc through anti-apoptotic functions, either encoded by the viral genome or induced by virus infection, in order for a BL to emerge has recently been re-emphasized [9, 10]. Our differential pathogenesis model for EBV-associated lymphomas, although controversial at first [11, 12, reviewed in 13], has gained strong support by recent large-scale epigenomic analyses: EBV-induced immortalization caused a massive demethylation of the B-cell genome affecting more than 2 GB of the genome and 1/3 of all genes . Contrary, primarily malignant lymphomas are characterized not by hypomethylation, but by a local hypermethylation of selected genomic loci [15-18].
EBV associated gastric carcinoma
Not only primarily malignant EBV associated lymphomas, but also NPC and EBVaGC are monoclonal proliferations of neoplastic cells that carry latent EBV genomes and display a characteristic hypermethylation of cellular promoters which is defined as CpG-island methylator phenotype (CIMP). NPC is an endemic tumor with a strong preference for South East Asia, especially Guangdong and Hong Kong, with an incidence rate of 20 to 30 cases per 100.000 persons per year, and virtually 100% of nonkeratinizing and undifferentiated NPCs are EBV-associated. Contrary, nearly 10% of the worldwide sporadic tumor gastric carcinoma (GC) are associated with EBV infection. Among gastric remnant carcinomas approximately 30% and among lymphoepithelioma-like GCs, approximately 80% are EBV-associated. Altogether, EBVaGC with an estimated more than 80.000 cases per year is the most frequent EBV-associated malignancy worldwide [reviewed in 18, 19].
1. Epstein MA, Achong BG, Barr YM: Virus particles in cultured lymphoblasts from Burkitt´s Lymphoma. Lancet 1964, 1:702-703.
2. zur Hausen H, Schulte-Holthausen H, Klein G, Henle W, Henle G, Clifford P, Santesson L: EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature 1970, 228:1056-1058.
3. Wolf H, zur Hausen H, Becker V: EB viral genomes in epithelial nasopharyngeal carcinoma cells. Nat New Biol 1973, 244:245-247.
4. Burke AP, Yen TS, Shekitka KM, Sobin LH: Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol 1990, 3:377-380.
5. Shibata D, Tokunaga M, Uemura Y, Sato E, Tanaka S, Weiss LM: Association of Epstein-Barr virus with undifferentiated gastric carcinomas with intense lymphoid infiltration. Lymphoepithelioma-like carcinoma. Am J Pathol 1991, 139:469-474.
6. Niller HH, Salamon D, Ilg K, Koroknai A, Banati F, Bauml G, Rucker O, Schwarzmann F, Wolf H, Minarovits J: The in vivo binding site for oncoprotein c-Myc in the promoter for Epstein-Barr virus (EBV) encoding RNA (EBER) 1 suggests a specific role for EBV in lymphomagenesis. Med Sci Monit 2003, 9:HY1-HY9.
7. Niller HH, Salamon D, Ilg K, Koroknai A, Banati F, Schwarzmann F, Wolf H, Minarovits J: EBV-associated neoplasms: alternative pathogenetic pathways. Med Hypotheses 2004, 62:387-391.30
8. Niller HH, Salamon D, Banati F, Schwarzmann F, Wolf H, Minarovits J: The LCR of EBV makes Burkitt's lymphoma endemic. Trends Microbiol 2004, 12:495-499.
9. Mbulaiteye SM: Burkitt Lymphoma: beyond discoveries. Infect Agent Cancer 2013, 8:35.
10. Westhoff Smith D, Sugden B: Potential cellular functions of Epstein-Barr Nuclear Antigen 1 (EBNA1) of Epstein-Barr Virus. Viruses 2013, 5:226-240.
11. Rossi G, Bonetti F: EBV and Burkitt's lymphoma. N Engl J Med 2004, 350:2621.
12. Thorley-Lawson DA: EBV and Burkitt's lymphoma. N Engl J Med 2004, 350:2621, author reply.
13. Niller HH, Banati F, Ay E, Minarovits J: Epigenetic changes in virus-associated neoplasms. In: Patho-Epigenetics of Disease. Edited by Minarovits J, Niller HH. New York: Springer; 2012, 179-225.
14. Hansen KD, Sabunciyan S, Langmead B, Nagy N, Curley R, Klein G, Klein E, Salamon D, Feinberg AP: Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization. Genome Res 2014, 24:177-184.
15. Martin-Subero JI, Ammerpohl O, Bibikova M, Wickham-Garcia E, Agirre X, Alvarez S, Bruggemann M, Bug S, Calasanz MJ, Deckert M et al: A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms. PLoS One 2009, 4:e6986.
16. Martin-Subero JI, Kreuz M, Bibikova M, Bentink S, Ammerpohl O, Wickham-Garcia E, Rosolowski M, Richter J, Lopez-Serra L, Ballestar E et al: New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling. Blood 2009, 113:2488-2497.
17. Kreck B, Richter J, Ammerpohl O, Barann M, Esser D, Petersen BS, Vater I, Murga Penas EM, Bormann Chung CA, Seisenberger S et al: Base-pair resolution DNA methylome of the EBV-positive Endemic Burkitt lymphoma cell line DAUDI determined by SOLiD bisulfite-sequencing. Leukemia 2013, 27:1751-1753.
18. Niller HH, Tarnai Z, Decsi G, Zsedenyi A, Szenthe K, Banati F, Minarovits J: The role of epigenetics in Epstein-Barr virus regulation and pathogenesis. Future Microbiol 2014, 9:747-756.
19. Niller HH, Banati F, Minarovits J: Epigenetic alterations in nasopharyngeal carcinoma and Epstein-Barr virus (EBV) associated gastric carcinoma: a lesson in contrasts. J Nasopharyng Carcinoma 2014, 1:e9.