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The curious case of the tumour virus: 50 years of Burkitt's lymphoma

An Erratum to this article was published on 15 December 2008

Key Points

  • Epstein–Barr virus (EBV) was discovered in Burkitt's lymphoma (BL), a tumour with some characteristics of germinal centre (GC) B lymphocytes, which led to the proposal that EBV was the first candidate human tumour virus. Subsequently, evidence accrued to support this notion, including the important fact that EBV could transform B lymphocytes in tissue culture (the growth transcription programme).

  • The 'EBV as BL tumour virus' hypothesis became confounded by a number of findings. These included the discovery that BL could occur without EBV, the fact that it was the deregulation of the cellular oncogene MYC through a translocation that was the defining defect in BL and that none of the EBV-transforming proteins was expressed in BL.

  • EBV was found to persist quiescently in resting, GC-derived memory B cells, in which none of the viral transforming proteins was expressed, just like BL. Consequently, a new model of EBV persistence was developed in which EBV used the growth transcription programme to transiently activate newly infected B cells so they could differentiate via the GC into the memory compartment.

  • It was established that deregulation of MYC by translocation not only drives proliferation but also induces apoptosis — this serves as a rate-limiting step in lymphomagenesis.

  • Gene-regulation experiments on the viral EBNA3 (EBV nuclear antigen 3) proteins revealed that they may play a part in transition from the growth programme through the GC and into memory. In parallel, they may epigenetically alter the cellular genome in such a way as to allow the infected cell to tolerate apoptosis caused by a deregulated MYC gene long after the viral genes cease expression.

  • The translocation event probably occurs in the GC, driven by AID (activation-induced cytidine deaminase) expression after the viral-transforming genes have been turned off. This cell then exits from the GC in an attempt to become a resting memory B cell, but is unable to do so because deregulated MYC keeps it proliferating.

  • Malaria is associated with the high incidence of EBV-positive BL in tropical Africa, but we know nothing about the underlying mechanism of this association. Malaria may increase both the frequency of spontaneous MYC translocations and the number of EBV-infected cells, thereby dramatically increasing the possibility that both MYC and EBV will occur in the same cell and lead to BL.

Abstract

Burkitt's lymphoma (BL) was first described 50 years ago, and the first human tumour virus Epstein–Barr virus (EBV) was discovered in BL tumours soon after. Since then, the role of EBV in the development of BL has become more and more enigmatic. Only recently have we finally begun to understand, at the cellular and molecular levels, the complex and interesting interaction of EBV with B cells that creates a predisposition for the development of BL. Here, we discuss the intertwined histories of EBV and BL and their relationship to the cofactors in BL pathogenesis: malaria and the MYC translocation.

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Figure 1: The current model of how EBV establishes and maintains persistent infection.
Figure 2: EBV uses the Notch system to autoregulate its growth.
Figure 3: Schematic of the proposed mechanism of EBV-positive Burkitt's lymphoma pathogenesis.

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Cristina López, Birgit Burkhardt, … Reiner Siebert

References

  1. Burkitt, D. A sarcoma involving the jaws in African children. Br. J. Surg. 46, 218–223 (1958).

    Article  CAS  PubMed  Google Scholar 

  2. Davies, J. N. et al. Cancer in an African community, 1897–1956. An analysis of the records of Mengo Hospital, Kampala, Uganda. I. Br. Med. J. 1, 259–264 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Griffin, B. E. & Rochford, R. in Epstein–Barr Virus (ed. Robertson, E. S.) 113–138 (Caister Academic, Norfolk, 2005).

    Google Scholar 

  4. Wright, D. H. The epidemiology of Burkitt's tumor. Cancer Res. 27, 2424–2438 (1967).

    CAS  PubMed  Google Scholar 

  5. Wright, D. H. Burkitt's lymphoma: a review of the pathology, immunology, and possible etiologic factors. Pathol. Annu. 6, 337–363 (1971).

    CAS  PubMed  Google Scholar 

  6. Epstein, M. A., Achong, B. G. & Barr, Y. M. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1, 702–703 (1964).

    Article  CAS  PubMed  Google Scholar 

  7. Henle, G. & Henle, W. Immunofluorescence in cells derived from Burkitt's lymphoma. J. Bacteriol. 91, 1248–1256 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Manolov, G. & Manolova, Y. Marker band in one chromosome 14 from Burkitt lymphomas. Nature 237, 33–34 (1972).

    Article  CAS  PubMed  Google Scholar 

  9. Klein, G. Specific chromosomal translocations and the genesis of B-cell-derived tumors in mice and men. Cell 32, 311–315 (1983).

    Article  CAS  PubMed  Google Scholar 

  10. Leder, P. in Burkitt's Lymphoma: a Human Cancer Model (eds Lenoir, G. M., O'Conor, G. T. & Olweny, C. L. M.) 341–371 (Oxford Univ. Press, New York, 1985).

    Google Scholar 

  11. Magrath, I. The pathogenesis of Burkitt's lymphoma. Adv. Cancer Res. 55, 133–270 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. de-The, G. et al. Epidemiological evidence for causal relationship between Epstein–Barr virus and Burkitt's lymphoma from Ugandan prospective study. Nature 274, 756–761 (1978).

    Article  CAS  PubMed  Google Scholar 

  13. Lindahl, T. et al. Covalently closed circular duplex DNA of Epstein–Barr virus in a human lymphoid cell line. J. Mol. Biol. 102, 511–530 (1976).

    Article  CAS  PubMed  Google Scholar 

  14. Reedman, B. M. & Klein, G. Cellular localisation of an Epstein–Barr virus (EBV) associated complement fixing antigen in producer and non-producer cell lines. Int. J. Cancer 1, 599–620 (1973).

    Google Scholar 

  15. Deyrup, A. T. Epstein–Barr virus-associated epithelial and mesenchymal neoplasms. Hum. Pathol. 39, 473–483 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Rickinson, A. B. & Kieff, E. D. in Virology Vol. 2 (eds Knipe, D. M. & Howley, P. M.) 2655–2700 (Lippincott Williams and Wilkins, New York, 2007).

    Google Scholar 

  17. Thorley-Lawson, D. A. in Epstein–Barr Virus (ed. Robertson, E. S.) 113–138 (Caister Academic, Norfolk, 2005).

    Google Scholar 

  18. Henle, W., Diehl, V., Kohn, G., Zur Hausen, H. & Henle, G. Herpes-type virus and chromosome marker in normal leukocytes after growth with irradiated Burkitt cells. Science 157, 1064–1065 (1967).

    Article  CAS  PubMed  Google Scholar 

  19. Kieff, E. D. in Virology Vol. 2 (eds Knipe, D. M. & Howley, P. M.) 2603–2655 (Lippincott Williams and Wilkins, New York, 2007).

    Google Scholar 

  20. Thorley-Lawson, D. A. & Mann, K. P. Early events in Epstein–Barr virus infection provide a model for B cell activation. J. Exp. Med. 162, 45–59 (1985).

    Article  CAS  PubMed  Google Scholar 

  21. Thorley-Lawson, D. A. Epstein–Barr virus: exploiting the immune system. Nature Rev. Immunol. 1, 75–82 (2001).

    Article  CAS  Google Scholar 

  22. Thorley-Lawson, D. A. & Gross, A. Persistence of the Epstein–Barr virus and the origins of associated lymphomas. N. Engl. J. Med. 350, 1328–1337 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Wang, D., Liebowitz, D. & Kieff, E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43, 831–840 (1985).

    Article  CAS  PubMed  Google Scholar 

  24. Robinson, J. E., Smith, D. & Niederman, J. Plasmacytic differentiation of circulating Epstein–Barr virus-infected B lymphocytes during acute infectious mononucleosis. J. Exp. Med. 153, 235–244 (1981).

    Article  CAS  PubMed  Google Scholar 

  25. Miyashita, E. M., Yang, B., Babcock, G. J. & Thorley-Lawson, D. A. Identification of the site of Epstein–Barr virus persistence in vivo as a resting B cell. J. Virol. 71, 4882–4891 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Miyashita, E. M., Yang, B., Lam, K. M., Crawford, D. H. & Thorley-Lawson, D. A. A novel form of Epstein–Barr virus latency in normal B cells in vivo. Cell 80, 593–601 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Khanna, R., Moss, D. J. & Burrows, S. R. Vaccine strategies against Epstein–Barr virus-associated diseases: lessons from studies on cytotoxic T-cell-mediated immune regulation. Immunol. Rev. 170, 49–64 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Hopwood, P. & Crawford, D. H. The role of EBV in post-transplant malignancies: a review. J. Clin. Pathol. 53, 248–254 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Babcock, G. J., Decker, L. L., Freeman, R. B. & Thorley-Lawson, D. A. Epstein–Barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. J. Exp. Med. 190, 567–576 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hecht, J. L. & Aster, J. C. Molecular biology of Burkitt's lymphoma. J. Clin. Oncol. 18, 3707–3721 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Nilsson, K. & Ponten, J. Classification and biological nature of established human hematopoietic cell lines. Int. J. Cancer 15, 321–341 (1975).

    Article  CAS  PubMed  Google Scholar 

  32. Gregory, C. D. et al. Identification of a subset of normal B cells with a Burkitt's lymphoma (BL)-like phenotype. J. Immunol. 139, 313–318 (1987).

    CAS  PubMed  Google Scholar 

  33. Schaefer, B. C., Strominger, J. L. & Speck, S. H. Redefining the Epstein–Barr virus-encoded nuclear antigen EBNA-1 gene promoter and transcription initiation site in group I Burkitt lymphoma cell lines. Proc. Natl Acad. Sci. USA 92, 10565–10569 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brooks, L., Yao, Q. Y., Rickinson, A. B. & Young, L. S. Epstein–Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J. Virol. 66, 2689–2697 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Deacon, E. M. et al. Epstein–Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J. Exp. Med. 177, 339–349 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Henle, W. & Henle, G. in The Epstein–Barr Virus (eds Epstein, M. A. & Achong, B. G.) 61–78 (Springer-Verlag, Berlin, 1979).

    Book  Google Scholar 

  37. Babcock, G. J., Decker, L. L., Volk, M. & Thorley-Lawson, D. A. EBV persistence in memory B cells in vivo. Immunity 9, 395–404 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Souza, T. A., Stollar, B. D., Sullivan, J. L., Luzuriaga, K. & Thorley-Lawson, D. A. Peripheral B cells latently infected with Epstein–Barr virus display molecular hallmarks of classical antigen-selected memory B cells. Proc. Natl Acad. Sci. USA 102, 18093–18098 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Souza, T. A., Stollar, B. D., Sullivan, J. L., Luzuriaga, K. & Thorley-Lawson, D. A. Influence of EBV on the peripheral blood memory B cell compartment. J. Immunol. 179, 3153–3160 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Hochberg, D. et al. Demonstration of the Burkitt's lymphoma Epstein–Barr virus phenotype in dividing latently infected memory cells in vivo. Proc. Natl Acad. Sci. USA 101, 239–244 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Pasqualucci, L. et al. AID is required for germinal center-derived lymphomagenesis. Nature Genet. 40, 108–112 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Klein, U. & Dalla-Favera, R. Germinal centres: role in B-cell physiology and malignancy. Nature Rev. Immunol. 8, 22–33 (2008).

    Article  CAS  Google Scholar 

  44. Dorsett, Y. et al. A role for AID in chromosome translocations between c-myc and the IgH variable region. J. Exp. Med. 204, 2225–2232 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bhatia, K. et al. Point mutations in the c-Myc transactivation domain are common in Burkitt's lymphoma and mouse plasmacytomas. Nature Genet. 5, 56–61 (1993).

    Article  CAS  PubMed  Google Scholar 

  46. Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    Article  CAS  PubMed  Google Scholar 

  47. Kovalchuk, A. L. et al. Burkitt lymphoma in the mouse. J. Exp. Med. 192, 1183–1190 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dang, C. V. et al. The c-Myc target gene network. Semin. Cancer Biol. 16, 253–264 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Zeller, K. I. et al. Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc. Natl Acad. Sci. USA 103, 17834–17839 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chang, T. C. et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nature Genet. 40, 43–50 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. O'Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Wade, M. & Wahl, G. M. c-Myc, genome instability, and tumorigenesis: the devil is in the details. Curr. Top. Microbiol. Immunol. 302, 169–203 (2006).

    CAS  PubMed  Google Scholar 

  53. Schlee, M. et al. c-MYC activation impairs the NF-κB and the interferon response: implications for the pathogenesis of Burkitt's lymphoma. Int. J. Cancer 120, 1387–1395 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Staege, M. S. et al. MYC overexpression imposes a nonimmunogenic phenotype on Epstein–Barr virus-infected B cells. Proc. Natl Acad. Sci. USA 99, 4550–4555 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kennedy, G., Komano, J. & Sugden, B. Epstein–Barr virus provides a survival factor to Burkitt's lymphomas. Proc. Natl Acad. Sci. USA 100, 14269–14274 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Komano, J., Maruo, S., Kurozumi, K., Oda, T. & Takada, K. Oncogenic role of Epstein–Barr virus-encoded RNAs in Burkitt's lymphoma cell line Akata. J. Virol. 73, 9827–9831 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ruf, I. K. et al. Epstein–Barr virus regulates c-MYC, apoptosis, and tumorigenicity in Burkitt lymphoma. Mol. Cell. Biol. 19, 1651–1660 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kelly, G. L., Milner, A. E., Baldwin, G. S., Bell, A. I. & Rickinson, A. B. Three restricted forms of Epstein–Barr virus latency counteracting apoptosis in c-myc-expressing Burkitt lymphoma cells. Proc. Natl Acad. Sci. USA 103, 14935–14940 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hurley, E. A. & Thorley-Lawson, D. A. B cell activation and the establishment of Epstein–Barr virus latency. J. Exp. Med. 168, 2059–2075 (1988).

    Article  CAS  PubMed  Google Scholar 

  60. Woisetschlaeger, M., Yandava, C. N., Furmanski, L. A., Strominger, J. L. & Speck, S. H. Promoter switching in Epstein–Barr virus during the initial stages of infection of B lymphocytes. Proc. Natl Acad. Sci. USA 87, 1725–1729 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Caldwell, R. G., Wilson, J. B., Anderson, S. J. & Longnecker, R. Epstein–Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9, 405–411 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Casola, S. et al. B cell receptor signal strength determines B cell fate. Nature Immunol. 5, 317–327 (2004).

    Article  CAS  Google Scholar 

  63. Gires, O. et al. Latent membrane protein 1 of Epstein–Barr virus mimics a constitutively active receptor molecule. EMBO J. 16, 6131–6140 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. He, B., Raab-Traub, N., Casali, P. & Cerutti, A. EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching. J. Immunol. 171, 5215–5224 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Panagopoulos, D., Victoratos, P., Alexiou, M., Kollias, G. & Mosialos, G. Comparative analysis of signal transduction by CD40 and the Epstein–Barr virus oncoprotein LMP1 in vivo. J. Virol. 78, 13253–13261 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ling, P. D., Hsieh, J. J., Ruf, I. K., Rawlins, D. R. & Hayward, S. D. EBNA-2 upregulation of Epstein–Barr virus latency promoters and the cellular CD23 promoter utilizes a common targeting intermediate, CBF1. J. Virol. 68, 5375–5383 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M. E. Notch signaling. Science 268, 225–232 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Tanigaki, K. & Honjo, T. Regulation of lymphocyte development by Notch signaling. Nature Immunol. 8, 451–456 (2007).

    Article  CAS  Google Scholar 

  69. Barolo, S., Stone, T., Bang, A. G. & Posakony, J. W. Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. Genes Dev. 16, 1964–1976 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chinnadurai, G. Transcriptional regulation by C-terminal binding proteins. Int. J. Biochem. Cell Biol. 39, 1593–1607 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Zimber-Strobl, U. et al. Epstein–Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP-Jκ, the homologue of Drosophila Suppressor of Hairless. EMBO J. 13, 4973–4982 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Radkov, S. A. et al. Epstein–Barr virus EBNA3C represses Cp, the major promoter for EBNA expression, but has no effect on the promoter of the cell gene CD21. J. Virol. 71, 8552–8562 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Le Roux, A., Kerdiles, B., Walls, D., Dedieu, J. F. & Perricaudet, M. The Epstein–Barr virus determined nuclear antigens EBNA-3A, -3B, and -3C repress EBNA-2-mediated transactivation of the viral terminal protein 1 gene promoter. Virology 205, 596–602 (1994).

    Article  CAS  PubMed  Google Scholar 

  74. Hickabottom, M., Parker, G. A., Freemont, P., Crook, T. & Allday, M. J. Two nonconsensus sites in the Epstein–Barr virus oncoprotein EBNA3A cooperate to bind the co-repressor carboxyl-terminal-binding protein (CtBP). J. Biol. Chem. 277, 47197–47204 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Touitou, R., Hickabottom, M., Parker, G., Crook, T. & Allday, M. J. Physical and functional interactions between the corepressor CtBP and the Epstein–Barr virus nuclear antigen EBNA3C. J. Virol. 75, 7749–7755 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Radkov, S. A. et al. Epstein–Barr virus nuclear antigen 3C interacts with histone deacetylase to repress transcription. J. Virol. 73, 5688–5697 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet. 33, 245–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Day, L. et al. Chromatin profiling of Epstein–Barr virus latency control region. J. Virol. 81, 6389–6401 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tao, Q. & Robertson, K. D. Stealth technology: how Epstein–Barr virus utilizes DNA methylation to cloak itself from immune detection. Clin. Immunol. 109, 53–63 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Paulson, E. J. & Speck, S. H. Differential methylation of Epstein–Barr virus latency promoters facilitates viral persistence in healthy seropositive individuals. J. Virol. 73, 9959–9968 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Casola, S. et al. B cell receptor signal strength determines B cell fate. Nature Immunol. 5, 317–327 (2004).

    Article  CAS  Google Scholar 

  82. Swanson-Mungerson, M., Bultema, R. & Longnecker, R. Epstein–Barr virus LMP2A enhances B-cell responses in vivo and in vitro. J. Virol. 80, 6764–6770 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Swanson-Mungerson, M. & Longnecker, R. Epstein–Barr virus latent membrane protein 2A and autoimmunity. Trends Immunol. 28, 213–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Swanson-Mungerson, M. A., Caldwell, R. G., Bultema, R. & Longnecker, R. Epstein–Barr virus LMP2A alters in vivo and in vitro models of B-cell anergy, but not deletion, in response to autoantigen. J. Virol. 79, 7355–7362 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kulwichit, W. et al. Expression of the Epstein–Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc. Natl Acad. Sci. USA 95, 11963–11968 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kis, L. L. et al. In vitro EBV-infected subline of KMH2, derived from Hodgkin lymphoma, expresses only EBNA-1, while CD40 ligand and IL-4 induce LMP-1 but not EBNA-2. Int. J. Cancer 113, 937–945 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Kis, L. L., Takahara, M., Nagy, N., Klein, G. & Klein, E. IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines. Blood 107, 2928–2935 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Konforte, D., Simard, N. & Paige, C. J. Interleukin-21 regulates expression of key Epstein–Barr virus oncoproteins, EBNA2 and LMP1, in infected human B cells. Virology 374, 100–113 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Allday, M. J., Sinclair, A., Parker, G., Crawford, D. H. & Farrell, P. J. Epstein–Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. EMBO J. 14, 1382–1391 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. O'Nions, J., Turner, A., Craig, R. & Allday, M. J. Epstein–Barr virus selectively deregulates DNA damage responses in normal B cells but has no detectable effect on regulation of the tumor suppressor p53. J. Virol. 80, 12408–12413 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Anderton, E. et al. Two Epstein–Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma. Oncogene 27, 421–433 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Kaiser, C. et al. The proto-oncogene c-myc is a direct target gene of Epstein–Barr virus nuclear antigen 2. J. Virol. 73, 4481–4484 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Rochford, R., Cannon, M. J. & Moormann, A. M. Endemic Burkitt's lymphoma: a polymicrobial disease? Nature Rev. Microbiol. 3, 182–187 (2005).

    Article  CAS  Google Scholar 

  94. Morrow, R. H. in Burkitt's Lymphoma: a Human Cancer Model (eds Lenoir, G. M., O'Conor, G. T. & Olweny, C. L. M.) 177–185 (Oxford Univ. Press, New York, 1985).

    Google Scholar 

  95. Geser, A., Brubaker, G. & Draper, C. C. Effect of a malaria suppression program on the incidence of African Burkitt's lymphoma. Am. J. Epidemiol. 129, 740–752 (1989).

    Article  CAS  PubMed  Google Scholar 

  96. Maclean, K. H., Dorsey, F. C., Cleveland, J. L. & Kastan, M. B. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J. Clin. Invest. 118, 79–88 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Moormann, A. M. et al. Exposure to holoendemic malaria results in elevated Epstein–Barr virus loads in children. J. Infect. Dis. 191, 1233–1238 (2005).

    Article  PubMed  Google Scholar 

  98. Moss, D. J. et al. A comparison of Epstein–Barr virus-specific T-cell immunity in malaria-endemic and -nonendemic regions of Papua New Guinea. Int. J. Cancer 31, 727–732 (1983).

    Article  CAS  PubMed  Google Scholar 

  99. Whittle, H. C. et al. The effects of Plasmodium falciparum malaria on immune control of B lymphocytes in Gambian children. Clin. Exp. Immunol. 80, 213–218 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ho, M. et al. Defective production of and response to IL-2 in acute human falciparum malaria. J. Immunol. 141, 2755–2759 (1988).

    CAS  PubMed  Google Scholar 

  101. Ho, M. et al. Antigen-specific immunosuppression in human malaria due to Plasmodium falciparum. J. Infect. Dis. 153, 763–771 (1986).

    Article  CAS  PubMed  Google Scholar 

  102. Donati, D. et al. Identification of a polyclonal B-cell activator in Plasmodium falciparum. Infect. Immun. 72, 5412–5418 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lenoir, G. M. & Bornkamm, G. W. Burkitt's lymphoma, a human cancer model for the study of the multistep development of cancer: proposal for a new scenario. Adv. Viral Oncol. 7, 173–206 (1987).

    CAS  Google Scholar 

  104. Biggar, R. J., Chaturvedi, A. K., Goedert, J. J. & Engels, E. A. AIDS-related cancer and severity of immunosuppression in persons with AIDS. J. Natl Cancer Inst. 99, 962–972 (2007).

    Article  PubMed  Google Scholar 

  105. Bloland, P. B. et al. Longitudinal cohort study of the epidemiology of malaria infections in an area of intense malaria transmission II. Descriptive epidemiology of malaria infection and disease among children. Am. J. Trop. Med. Hyg. 60, 641–648 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Clybouw, C. et al. EBV infection of human B lymphocytes leads to down-regulation of Bim expression: relationship to resistance to apoptosis. J. Immunol. 175, 2968–2973 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Kelly, G. L. et al. Epstein–Barr virus nuclear antigen 2 (EBNA2) gene deletion is consistently linked with EBNA3A, -3B, and -3C expression in Burkitt's lymphoma cells and with increased resistance to apoptosis. J. Virol. 79, 10709–10717 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Knight, J. S. & Robertson, E. S. in Epstein–Barr Virus (ed. Robertson, E. S.) 501–532 (Caister Academic, Norfolk, 2005).

    Google Scholar 

  109. O'Nions, J. & Allday, M. J. Deregulation of the cell cycle by the Epstein–Barr virus. Adv. Cancer Res. 92, 119–186 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Kamranvar, S. A., Gruhne, B., Szeles, A. & Masucci, M. G. Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma. Oncogene 26, 5115–5123 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. van den Bosch, C. & Lloyd, G. Chikungunya fever as a risk factor for endemic Burkitt's lymphoma in Malawi. Trans. R. Soc. Trop. Med. Hyg. 94, 704–705 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Imai, S. et al. African Burkitt's lymphoma: a plant, Euphorbia tirucalli, reduces Epstein–Barr virus-specific cellular immunity. Anticancer Res. 14, 933–936 (1994).

    CAS  PubMed  Google Scholar 

  113. Burkhardt, B. et al. The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br. J. Haematol. 131, 39–49 (2005).

    Article  PubMed  Google Scholar 

  114. Sandlund, J. T., Downing, J. R. & Crist, W. M. Non-Hodgkin's lymphoma in childhood. N. Engl. J. Med. 334, 1238–1248 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. Kuppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Shaffer, A. L., Rosenwald, A. & Staudt, L. M. Lymphoid malignancies: the dark side of B-cell differentiation. Nature Rev. Immunol. 2, 920–932 (2002).

    Article  CAS  Google Scholar 

  117. Onizuka, T. et al. BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. Blood 86, 28–37 (1995).

    CAS  PubMed  Google Scholar 

  118. Dave, S. S. et al. Molecular diagnosis of Burkitt's lymphoma. N. Engl. J. Med. 354, 2431–2442 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Klein, U. et al. Transcriptional analysis of the B cell germinal center reaction. Proc. Natl Acad. Sci. USA 100, 2639–2644 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Shaffer, A. L. et al. Signatures of the immune response. Immunity 15, 375–385 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Haluska, F. G., Finver, S., Tsujimoto, Y. & Croce, C. M. The t(8; 14) chromosomal translocation occurring in B-cell malignancies results from mistakes in V-D-J joining. Nature 324, 158–161 (1986).

    Article  CAS  PubMed  Google Scholar 

  122. Bellan, C. et al. Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas. Blood 106, 1031–1036 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Potter, M. & Wiener, F. Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13, 1681–1697 (1992).

    Article  CAS  PubMed  Google Scholar 

  124. Harrington, E. A., Fanidi, A. & Evan, G. I. Oncogenes and cell death. Curr. Opin. Genet. Dev. 4, 120–129 (1994).

    Article  CAS  PubMed  Google Scholar 

  125. Eischen, C. M., Weber, J. D., Roussel, M. F., Sherr, C. J. & Cleveland, J. L. Disruption of the ARF–Mdm2–p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 13, 2658–2669 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lindstrom, M. S. & Wiman, K. G. Role of genetic and epigenetic changes in Burkitt lymphoma. Semin. Cancer Biol. 12, 381–387 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Strasser, A. The role of BH3-only proteins in the immune system. Nature Rev. Immunol. 5, 189–200 (2005).

    Article  CAS  Google Scholar 

  128. Egle, A., Harris, A. W., Bath, M. L., O'Reilly, L. & Cory, S. VavP–Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103, 2276–2283 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Mestre-Escorihuela, C. et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 109, 271–280 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Tagawa, H. et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 24, 1348–1358 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Dang, C. V., O'Donnell, K. A. & Juopperi, T. The great MYC escape in tumorigenesis. Cancer Cell 8, 177–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Hemann, M. T. et al. Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 436, 807–811 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bhende, P. M., Dickerson, S. J., Sun, X., Feng, W. H. & Kenney, S. C. X-box-binding protein 1 activates lytic Epstein–Barr virus gene expression in combination with protein kinase D. J. Virol. 81, 7363–7370 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Laichalk, L. L. & Thorley-Lawson, D. A. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein–Barr virus in vivo. J. Virol. 79, 1296–1307 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sun, C. C. & Thorley-Lawson, D. A. Plasma cell-specific transcription factor XBP-1s binds to and transactivates the Epstein–Barr virus BZLF1 promoter. J. Virol. 81, 13566–13577 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

D.A.T.-L. is supported by Public Health Services grants CA 65883, AI 18757 and AI 062989. M.J.A. is supported by the Wellcome Trust and the Medical Research Council.

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EBV latent transcription programs, latent genes and their functions. (PDF 161 kb)

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Glossary

EBNA1

(EBV nuclear antigen 1). Responsible for replicating and tethering the viral genome to ensure its segregation.

EBNA2

(EBV nuclear antigen 2). Transcription factor that is responsible for transactivating the promoters of the viral genes expressed in the growth programme. Functional homologue of NotchIC. Upregulates MYC expression

Lymphoblast

An activated lymphocyte.

LMP1

(Latent membrane protein 1). Provides a constitutive T-helper cell signal that may help to rescue Epstein–Barr virus infected germinal-centre cells and drive them into the memory compartment. LMP1 downregulates BCL6 and induces AID (activation-induced cytidine deaminase).

Germinal centre

The region in a lymph node where antigen-activated B cells proliferate, actively mutate and isotype switch their immunoglobulin genes.

Activation marker

A molecule expressed on the surface of lymphocytes when they become lymphoblasts.

Isotype switching

The process by which immunoglobulins change their isotype.

Somatic hypermutation

The process by which immunoglobulins have their affinity for antigen altered by mutations that target the antibody-combining site.

Antigen selection

The process by which B cells that have undergone somatic hypermutation of their immunoglobulins in a germinal centre compete to bind antigen.

AID

(Activation-induced cytidine deaminase). An enzyme that is essential for catalysing isotype switching and somatic hypermutations, and is highly expressed in germinal centres.

Waldeyer's ring

The ring of lymphoid tissue at the back of the mouth that includes the adenoids and the five tonsils (lingual and paired palatine and tubal).

Follicle

The region of lymph nodes where naive B cells migrate, proliferate and expand to form a germinal centre if they encounter antigen.

EBNA3A and EBNA3C

(EBV nuclear antigen 3A and 3C). Negative regulators of EBNA2 that are thought to be involved in the transition from the growth programme to the default programme through the epigenetic silencing of the C and W promoters. EBNA3A and EBNA3C are functional homologues of the Drosophila gene Hairless and downregulate BIM.

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Thorley-Lawson, D., Allday, M. The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nat Rev Microbiol 6, 913–924 (2008). https://doi.org/10.1038/nrmicro2015

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