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

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.

[1]  S. Burrows,et al.  Vaccine strategies against Epstein‐Barr virus‐associated diseases: lessons from studies on cytotoxic T‐cell‐mediated immune regulation , 1999, Immunological reviews.

[2]  Kathryn A. O’Donnell,et al.  The great MYC escape in tumorigenesis. , 2005, Cancer cell.

[3]  J. Downing,et al.  Non-Hodgkin's lymphoma in childhood. , 1996, The New England journal of medicine.

[4]  B. Stollar,et al.  Influence of EBV on the Peripheral Blood Memory B Cell Compartment1 , 2007, The Journal of Immunology.

[5]  M. Perricaudet,et al.  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. , 1994, Virology.

[6]  Bin Yang,et al.  Identification of the Site of Epstein-Barr Virus Persistence In Vivo as a Resting B Cell , 1998, Journal of Virology.

[7]  M. Allday,et al.  Epstein-Barr Virus Selectively Deregulates DNA Damage Responses in Normal B Cells but Has No Detectable Effect on Regulation of the Tumor Suppressor p53 , 2006, Journal of Virology.

[8]  A. Deyrup Progress in pathology Epstein-Barr virus – associated epithelial and mesenchymal neoplasms , 2008 .

[9]  R. Palmiter,et al.  The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice , 1985, Nature.

[10]  D. Thorley-Lawson,et al.  Early events in Epstein-Barr virus infection provide a model for B cell activation , 1985, The Journal of experimental medicine.

[11]  C. van den Bosch,et al.  Chikungunya fever as a risk factor for endemic Burkitt's lymphoma in Malawi. , 2000, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[12]  Juan F. García,et al.  Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. , 2007, Blood.

[13]  G. Klein,et al.  Cellular localization of an Epstein‐Barr virus (EBV)‐associated complement‐fixing antigen in producer and non‐producer lymphoblastoid cell lines , 1973, International journal of cancer.

[14]  B. Burkhardt,et al.  The impact of age and gender on biology, clinical features and treatment outcome of non‐Hodgkin lymphoma in childhood and adolescence , 2005, British journal of haematology.

[15]  P. Freemont,et al.  Two Nonconsensus Sites in the Epstein-Barr Virus Oncoprotein EBNA3A Cooperate to Bind the Co-repressor Carboxyl-terminal-binding Protein (CtBP)* , 2002, The Journal of Biological Chemistry.

[16]  D. Thorley-Lawson,et al.  B cell activation and the establishment of Epstein-Barr virus latency , 1988, The Journal of experimental medicine.

[17]  M. Lipinski,et al.  Identification of a subset of normal B cells with a Burkitt's lymphoma (BL)-like phenotype. , 1987, Journal of immunology.

[18]  S. Kenney,et al.  X-Box-Binding Protein 1 Activates Lytic Epstein-Barr Virus Gene Expression in Combination with Protein Kinase D , 2007, Journal of Virology.

[19]  J. Hsieh,et al.  EBNA-2 upregulation of Epstein-Barr virus latency promoters and the cellular CD23 promoter utilizes a common targeting intermediate, CBF1 , 1994, Journal of virology.

[20]  John L Cleveland,et al.  Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. , 2008, The Journal of clinical investigation.

[21]  R. Owor,et al.  Cancer in an African Community, 1897–1956 , 1964, British medical journal.

[22]  Riccardo Dalla-Favera,et al.  Germinal centres: role in B-cell physiology and malignancy , 2008, Nature Reviews Immunology.

[23]  I. Mackay,et al.  Australia Antigen in Chronic Hepatitis in Australia* , 1970, British medical journal.

[24]  A. Polack,et al.  MYC overexpression imposes a nonimmunogenic phenotype on Epstein–Barr virus-infected B cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  T. Honjo,et al.  Epstein‐Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP‐J kappa, the homologue of Drosophila Suppressor of Hairless. , 1994, The EMBO journal.

[26]  J. Sample,et al.  Epstein-Barr Virus Regulates c-MYC, Apoptosis, and Tumorigenicity in Burkitt Lymphoma , 1999, Molecular and Cellular Biology.

[27]  D. Wright Burkitt's lymphoma: a review of the pathology, immunology, and possible etiologic factors. , 1971, Pathology annual.

[28]  S. Maruo,et al.  Oncogenic Role of Epstein-Barr Virus-Encoded RNAs in Burkitt’s Lymphoma Cell Line Akata , 1999, Journal of Virology.

[29]  P. Lieberman,et al.  Chromatin Profiling of Epstein-Barr Virus Latency Control Region , 2007, Journal of Virology.

[30]  B. Sugden,et al.  Epstein-Barr virus provides a survival factor to Burkitt's lymphomas , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  G. Parker,et al.  Epstein‐Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. , 1995, The EMBO journal.

[32]  T. Crook,et al.  Physical and Functional Interactions between the Corepressor CtBP and the Epstein-Barr Virus Nuclear Antigen EBNA3C , 2001, Journal of Virology.

[33]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[34]  W. Henle,et al.  Seroepidemiology of the Virus , 1979 .

[35]  M. Potter,et al.  Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. , 1992, Carcinogenesis.

[36]  P. Casali,et al.  EBV-Encoded Latent Membrane Protein 1 Cooperates with BAFF/BLyS and APRIL to Induce T Cell-Independent Ig Heavy Chain Class Switching 1 , 2003, The Journal of Immunology.

[37]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[38]  Andrea Califano,et al.  Transcriptional analysis of the B cell germinal center reaction , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  H. Webster,et al.  Antigen-specific immunosuppression in human malaria due to Plasmodium falciparum. , 1986, The Journal of infectious diseases.

[40]  A. W. Harris,et al.  VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. , 2004, Blood.

[41]  R. Longnecker,et al.  Epstein-Barr Virus LMP2A Alters In Vivo and In Vitro Models of B-Cell Anergy, but Not Deletion, in Response to Autoantigen , 2005, Journal of Virology.

[42]  J. Aster,et al.  Molecular biology of Burkitt's lymphoma. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  L. Staudt,et al.  Signatures of the immune response. , 2001, Immunity.

[44]  I. Magrath The pathogenesis of Burkitt's lymphoma. , 1990, Advances in cancer research.

[45]  D. Thorley-Lawson,et al.  Persistence of the Epstein-Barr virus and the origins of associated lymphomas. , 2004, The New England journal of medicine.

[46]  S. Mori,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. , 1995, Blood.

[47]  A. Strasser The role of BH3-only proteins in the immune system , 2005, Nature Reviews Immunology.

[48]  J. Pontén,et al.  Classification and biological nature of established human hematopoietic cell lines , 1975, International journal of cancer.

[49]  I. Magrath,et al.  Point mutations in the c–Myc transactivation domain are common in Burkitt's lymphoma and mouse plasmacytomas , 1993, Nature Genetics.

[50]  A. Rickinson,et al.  Three restricted forms of Epstein–Barr virus latency counteracting apoptosis in c-myc-expressing Burkitt lymphoma cells , 2006, Proceedings of the National Academy of Sciences.

[51]  G. Evan,et al.  Oncogenes and cell death. , 1994, Current opinion in genetics & development.

[52]  Wright Dh The epidemiology of Burkitt's tumor. , 1967 .

[53]  G. Kollias,et al.  Comparative Analysis of Signal Transduction by CD40 and the Epstein-Barr Virus Oncoprotein LMP1 In Vivo , 2004, Journal of Virology.

[54]  P. Sträuli,et al.  Transplantation behavior and cytogenetic characteristics of a spontaneous reticulum cell sarcoma in the golden hamster , 1966, International journal of cancer.

[55]  M. Ueffing,et al.  Latent membrane protein 1 of Epstein–Barr virus mimics a constitutively active receptor molecule , 1997, The EMBO journal.

[56]  P. Isaacson Burkitt's Lymphoma: A Human Cancer Model , 1986 .

[57]  S. Speck,et al.  Differential Methylation of Epstein-Barr Virus Latency Promoters Facilitates Viral Persistence in Healthy Seropositive Individuals , 1999, Journal of Virology.

[58]  W. Hawley,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. , 1999, The American journal of tropical medicine and hygiene.

[59]  W. Henle,et al.  Immunofluorescence in Cells Derived from Burkitt's Lymphoma , 1966, Journal of bacteriology.

[60]  M. Masucci,et al.  Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma , 2007, Oncogene.

[61]  E. Lennette,et al.  The Epstein-Barr virus. , 1979, Scientific American.

[62]  D. Thorley-Lawson,et al.  Terminal Differentiation into Plasma Cells Initiates the Replicative Cycle of Epstein-Barr Virus In Vivo , 2005, Journal of Virology.

[63]  J. Kutok,et al.  B cell receptor signal strength determines B cell fate , 2004, Nature Immunology.

[64]  D. Burkitt A sarcoma involving the jaws in african children , 1972, The British journal of surgery.

[65]  P. Farrell,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 , 1997, Journal of virology.

[66]  B. Stollar,et al.  Peripheral B cells latently infected with Epstein-Barr virus display molecular hallmarks of classical antigen-selected memory B cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[67]  E. Kieff,et al.  An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells , 1985, Cell.

[68]  M. Bourgeade,et al.  EBV Infection of Human B Lymphocytes Leads to Down-Regulation of Bim Expression: Relationship to Resistance to Apoptosis1 , 2005, The Journal of Immunology.

[69]  T. Honjo,et al.  Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme , 2000, Cell.

[70]  B. Kempkes,et al.  The Proto-Oncogene c-myc Is a Direct Target Gene of Epstein-Barr Virus Nuclear Antigen 2 , 1999, Journal of Virology.

[71]  D. Crawford,et al.  The role of EBV in post-transplant malignancies: a review , 2000, Journal of clinical pathology.

[72]  S. Barolo,et al.  Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. , 2002, Genes & development.

[73]  J. Gavin,et al.  A SCANNING ELECTRON MICROSCOPE STUDY OF LYMPHOCYTE‐ERYTHROCYTE BINDING IN THREE TYPES OF ROSETTE , 1974, Pathology.

[74]  D. Thorley-Lawson,et al.  A novel form of Epstein-Barr virus latency in normal B cells in vivo , 1995, Cell.

[75]  M. Roussel,et al.  Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. , 1999, Genes & development.

[76]  Q Y Yao,et al.  Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts , 1992, Journal of virology.

[77]  G. Klein Specific chromosomal translocations and the genesis of B-cell-derived tumors in mice and men , 1983, Cell.

[78]  V. Godfrey,et al.  Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[79]  G. Klein,et al.  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. , 2006, Blood.

[80]  T. Kouzarides,et al.  Epstein-Barr Virus Nuclear Antigen 3C Interacts with Histone Deacetylase To Repress Transcription , 1999, Journal of Virology.

[81]  S. Pileri,et al.  Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas. , 2005, Blood.

[82]  A. Geser,et al.  Effect of a malaria suppression program on the incidence of African Burkitt's lymphoma. , 1989, American journal of epidemiology.

[83]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[84]  M. Epstein,et al.  VIRUS PARTICLES IN CULTURED LYMPHOBLASTS FROM BURKITT'S LYMPHOMA. , 1964, Lancet.

[85]  G. Wahl,et al.  c-Myc, genome instability, and tumorigenesis: the devil is in the details. , 2006, Current topics in microbiology and immunology.

[86]  A. Moormann,et al.  Endemic Burkitt's lymphoma: a polymicrobial disease? , 2005, Nature Reviews Microbiology.

[87]  C. Paige,et al.  Interleukin-21 regulates expression of key Epstein-Barr virus oncoproteins, EBNA2 and LMP1, in infected human B cells. , 2008, Virology.

[88]  L. Staudt,et al.  c‐MYC activation impairs the NF‐κB and the interferon response: Implications for the pathogenesis of Burkitt's lymphoma , 2007, International journal of cancer.

[89]  M. Wahlgren,et al.  Identification of a Polyclonal B-Cell Activator in Plasmodium falciparum , 2004, Infection and Immunity.

[90]  D. Thorley-Lawson,et al.  EBV persistence in memory B cells in vivo. , 1998, Immunity.

[91]  J. Strominger,et al.  Promoter switching in Epstein-Barr virus during the initial stages of infection of B lymphocytes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[92]  L. Staudt,et al.  Decision making in the immune system: Lymphoid Malignancies: the dark side of B-cell differentiation , 2002, Nature Reviews Immunology.

[93]  D. Thorley-Lawson,et al.  Epstein-Barr virus: exploiting the immune system , 2001, Nature Reviews Immunology.

[94]  Katherine Luzuriaga,et al.  Demonstration of the Burkitt's lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cells in vivo , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Q. Tao,et al.  Stealth technology: how Epstein-Barr virus utilizes DNA methylation to cloak itself from immune detection. , 2003, Clinical immunology.

[96]  H. Ohigashi,et al.  African Burkitt's lymphoma: a plant, Euphorbia tirucalli, reduces Epstein-Barr virus-specific cellular immunity. , 1994, Anticancer research.

[97]  J. Robinson,et al.  Plasmacytic differentiation of circulating Epstein-Barr virus-infected B lymphocytes during acute infectious mononucleosis , 1981, The Journal of experimental medicine.

[98]  T. Lindahl,et al.  Covalently closed circular duplex DNA of Epstein-Barr virus in a human lymphoid cell line. , 1976, Journal of molecular biology.

[99]  H. Tagawa,et al.  Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM , 2005, Oncogene.

[100]  D. Thorley-Lawson,et al.  Plasma Cell-Specific Transcription Factor XBP-1s Binds to and Transactivates the Epstein-Barr Virus BZLF1 Promoter , 2007, Journal of Virology.

[101]  Zhiping Weng,et al.  Global mapping of c-Myc binding sites and target gene networks in human B cells , 2006, Proceedings of the National Academy of Sciences.

[102]  Chen-feng Qi,et al.  Burkitt Lymphoma in the Mouse , 2000, The Journal of experimental medicine.

[103]  H. Webster,et al.  Defective production of and response to IL-2 in acute human falciparum malaria. , 1988, Journal of immunology.

[104]  M. Allday,et al.  Deregulation of the cell cycle by the Epstein-Barr virus. , 2004, Advances in cancer research.

[105]  L. Pasqualucci,et al.  AID is required for germinal center–derived lymphomagenesis , 2008, Nature Genetics.

[106]  T. Honjo,et al.  Regulation of lymphocyte development by Notch signaling , 2007, Nature Immunology.

[107]  F. Haluska,et al.  The t(8; 14) chromosomal translocation occurring in B-cell malignancies results from mistakes in V–D–J joining , 1986, Nature.

[108]  L. Young,et al.  Epstein-Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells , 1993, The Journal of experimental medicine.

[109]  Riccardo Dalla-Favera,et al.  Mechanisms of chromosomal translocations in B cell lymphomas , 2001, Oncogene.

[110]  R. Longnecker,et al.  Epstein-Barr virus latent membrane protein 2A and autoimmunity. , 2007, Trends in immunology.

[111]  S. Anderson,et al.  Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. , 1998, Immunity.

[112]  M. Fortini,et al.  Notch signaling. , 1995, Science.

[113]  J. Kazura,et al.  Exposure to holoendemic malaria results in elevated Epstein-Barr virus loads in children. , 2005, The Journal of infectious diseases.

[114]  G. Chinnadurai Transcriptional regulation by C-terminal binding proteins. , 2007, The international journal of biochemistry & cell biology.

[115]  V. Diehl,et al.  Herpes-Type Virus and Chromosome Marker in Normal Leukocytes after Growth with Irradiated Burkitt Cells , 1967, Science.

[116]  J. Goedert,et al.  AIDS-related cancer and severity of immunosuppression in persons with AIDS. , 2007, Journal of the National Cancer Institute.

[117]  J. Strominger,et al.  Redefining the Epstein-Barr virus-encoded nuclear antigen EBNA-1 gene promoter and transcription initiation site in group I Burkitt lymphoma cell lines. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[118]  M. Nussenzweig,et al.  A role for AID in chromosome translocations between c-myc and the IgH variable region , 2007, Journal of Experimental Medicine.

[119]  R. Longnecker,et al.  Epstein-Barr Virus LMP2A Enhances B-Cell Responses In Vivo and In Vitro , 2006, Journal of Virology.

[120]  M. Lindström,et al.  Role of genetic and epigenetic changes in Burkitt lymphoma. , 2002, Seminars in cancer biology.

[121]  N. Day,et al.  Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt's lymphoma from Ugandan prospective study , 1978, Nature.

[122]  D. Wright The epidemiology of Burkitt's tumor. , 1967, Cancer research.

[123]  S. Lowe,et al.  Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants , 2005, Nature.

[124]  Kenji Matsuno,et al.  Notch signaling. , 1995, Science.

[125]  Robert E. White,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 , 2008, Oncogene.

[126]  G. Klein,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 , 2005, International journal of cancer.

[127]  Richard Simon,et al.  Molecular diagnosis of Burkitt's lymphoma. , 2006, The New England journal of medicine.

[128]  W. Hammerschmidt,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 , 2005, Journal of Virology.

[129]  G. Manolov,et al.  Marker Band in One Chromosome 14 from Burkitt Lymphomas , 1972, Nature.

[130]  H. Whittle,et al.  The effects of Plasmodium falciparum malaria on immune control of B lymphocytes in Gambian children , 1990, Clinical and experimental immunology.

[131]  T. Crook,et al.  Physical and Functional Interactions between the Corepressor CtBP and the Epstein-Barr Virus Nuclear Antigen EBNA 3 C , 2001 .

[132]  Kathryn A. O’Donnell,et al.  The c-Myc target gene network. , 2006, Seminars in cancer biology.

[133]  J. H. Pope,et al.  A comparison of epstein‐barr virus‐specific T‐cell immunity in malaria‐endemic and ‐nonendemic regions of Papua New Guinea , 1983, International journal of cancer.

[134]  R. Owor,et al.  Cancer in an African Community, 1897–1956* , 1964 .

[135]  R. Freeman,et al.  Epstein-Barr Virus–Infected Resting Memory B Cells, Not Proliferating Lymphoblasts, Accumulate in the Peripheral Blood of Immunosuppressed Patients , 1999, The Journal of experimental medicine.

[136]  R. Longnecker,et al.  Epstein-barr Virus Lmp2a Enhances B-cell , 2006 .