Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Epstein–Barr virus LMP2A accelerates MYC-induced lymphomagenesis

Oncogene volume 28, pages 1471–1476 (2009)Cite this article

Abstract

Despite the identification of Epstein–Barr virus (EBV) in tumors of Burkitt's lymphoma (BL) over 40 years ago, the exact contribution of EBV to BL is undefined. EBV encodes for multiple proteins in latent B cells that affect B cell survival and activation. One such protein, latent membrane protein 2A (LMP2A), protects B cells from numerous pro-apoptotic stimuli. Therefore, we tested whether LMP2A protects B cells from apoptosis induced by aberrant c-MYC expression that precedes and dominates BL. We crossed LMP2A-transgenic mice (LMP2A-Tg), in which all B cells express LMP2A, to a transgenic mouse that expresses a BL translocation of myc (λ-MYC-Tg mice). LMP2A promotes proliferation and protects B cells from MYC-induced apoptosis in λ-MYC-Tg mice. LMP2A also accelerates the development of lymphoma in LMP2A/λ-MYC-Tg mice. Finally, LMP2A increases the expression of Bcl-XL in both pre-tumor B cells and tumor cells, suggesting a mechanism for LMP2A-mediated B cell survival in the presence of MYC. These results support a hypothesis that EBV LMP2A promotes tumor development by protecting pre-tumor B cells that would normally apoptose after the c-myc translocation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Anderson LJ, Longnecker R . (2008). EBV LMP2A provides a surrogate pre-B cell receptor signal through constitutive activation of the ERK/MAPK pathway. J Gen Virol 89: 1563–1568.

    Article  CAS  Google Scholar 

  • Babcock GJ, Hochberg D, Thorley-Lawson AD . (2000). The expression pattern of Epstein–Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13: 497–506.

    Article  CAS  Google Scholar 

  • Bell AI, Groves K, Kelly GL, Croom-Carter D, Hui E, Chan AT et al. (2006). Analysis of Epstein–Barr virus latent gene expression in endemic Burkitt's lymphoma and nasopharyngeal carcinoma tumour cells by using quantitative real-time PCR assays. J Gen Virol 87: 2885–2890.

    Article  CAS  Google Scholar 

  • Caldwell RG, Wilson JB, Anderson SJ, Longnecker R . (1998). Epstein–Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9: 405–411.

    Article  CAS  Google Scholar 

  • Chen SY, Lu J, Shih YC, Tsai CH . (2002). Epstein–Barr virus latent membrane protein 2A regulates c-Jun protein through extracellular signal-regulated kinase. J Virol 76: 9556–9561.

    Article  CAS  Google Scholar 

  • Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM . (1982). Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA 79: 7824–7827.

    Article  CAS  Google Scholar 

  • Egle A, Harris AW, Bouillet P, Cory S . (2004). Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA 101: 6164–6169.

    Article  CAS  Google Scholar 

  • Eischen CM, Woo D, Roussel MF, Cleveland JL . (2001). Apoptosis triggered by Myc-induced suppression of Bcl-X(L) or Bcl-2 is bypassed during lymphomagenesis. Mol Cell Biol 21: 5063–5070.

    Article  CAS  Google Scholar 

  • Epstein MA, Achong BG, Barr YM . (1964). Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1: 702–703.

    Article  CAS  Google Scholar 

  • Fukuda M, Longnecker R . (2004). Latent membrane protein 2A inhibits transforming growth factor-beta 1-induced apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. J Virol 78: 1697–1705.

    Article  CAS  Google Scholar 

  • Garrison SP, Jeffers JR, Yang C, Nilsson JA, Hall MA, Rehg JE et al. (2008). Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol Cell Biol 28: 5391–5402.

    Article  CAS  Google Scholar 

  • Gerbitz A, Mautner J, Geltinger C, Hortnagel K, Christoph B, Asenbauer H et al. (1999). Deregulation of the proto-oncogene c-myc through t(8;22) translocation in Burkitt's lymphoma. Oncogene 18: 1745–1753.

    Article  CAS  Google Scholar 

  • Harris AW, Pinkert CA, Crawford M, Langdon WY, Brinster RL, Adams JM . (1988). The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J Exp Med 167: 353–371.

    Article  CAS  Google Scholar 

  • Hemann MT, Bric A, Teruya-Feldstein J, Herbst A, Nilsson JA, Cordon-Cardo C et al. (2005). Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 436: 807–811.

    Article  CAS  Google Scholar 

  • Hsu JL, Glaser SL . (2000). Epstein–Barr virus-associated malignancies: epidemiologic patterns and etiologic implications. Crit Rev Oncol Hematol 34: 27–53.

    Article  CAS  Google Scholar 

  • Ikeda A, Merchant M, Lev L, Longnecker R, Ikeda M . (2004). Latent membrane protein 2A, a viral B cell receptor homologue, induces CD5+ B-1 cell development. J Immunol 172: 5329–5337.

    Article  CAS  Google Scholar 

  • Kim JS, Han SS, Park SS, McNeil N, Janz S . (2006). Plasma cell tumour progression in iMycEmu gene-insertion mice. J Pathol 209: 44–55.

    Article  CAS  Google Scholar 

  • Kovalchuk AL, Qi CF, Torrey TA, Taddesse-Heath L, Feigenbaum L, Park SS et al. (2000). Burkitt lymphoma in the mouse. J Exp Med 192: 1183–1190.

    Article  CAS  Google Scholar 

  • Kurth J, Spieker T, Wustrow J, Strickler GJ, Hansmann LM, Rajewsky K et al. (2000). EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity 13: 485–495.

    Article  CAS  Google Scholar 

  • Linden M, Kirchhof N, Carlson C, Van Ness B . (2004). Targeted overexpression of Bcl-XL in B-lymphoid cells results in lymphoproliferative disease and plasma cell malignancies. Blood 103: 2779–2786.

    Article  CAS  Google Scholar 

  • Mancao C, Altmann M, Jungnickel B, Hammerschmidt W . (2005). Rescue of ‘crippled’ germinal center B cells from apoptosis by Epstein–Barr virus. Blood 106: 4339–4344.

    Article  CAS  Google Scholar 

  • Mancao C, Hammerschmidt W . (2007). Epstein–Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110: 3715–3721.

    Article  CAS  Google Scholar 

  • Newman SC . (2003). Biostatistical Methods in Epidemiology. John Wiley and Sons Inc.: New York, NY.

    Google Scholar 

  • Nilsson JA, Cleveland JL . (2003). Myc pathways provoking cell suicide and cancer. Oncogene 22: 9007–9021.

    Article  CAS  Google Scholar 

  • Pan YR, Vatsyayan J, Chang YS, Chang HY . (2008). Epstein–Barr virus latent membrane protein 2A upregulates UDP-glucose dehydrogenase gene expression via ERK and PI3K/Akt pathway. Cell Microbiol 10: 2447–2460.

    Article  CAS  Google Scholar 

  • Panousis CG, Rowe DT . (1997). Epstein–Barr virus latent membrane protein 2 associates with and is a substrate for mitogen-activated protein kinase. J Virol 71: 4752–4760.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park SS, Kim JS, Tessarollo L, Owens JD, Peng L, Han SS et al. (2005). Insertion of c-Myc into IgH induces B-cell and plasma-cell neoplasms in mice. Cancer Res 65: 1306–1315.

    Article  CAS  Google Scholar 

  • Portis T, Longnecker R . (2004). Epstein–Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/AKT pathway. Oncogene 23: 8619–8628.

    Article  CAS  Google Scholar 

  • Rickinson ABaEK . (2007). Epstein–Barr Virus. Lippincott-Raven Publishers II: Philadelphia, PA.

    Google Scholar 

  • Swanson PJ, Kuslak SL, Fang W, Tze L, Gaffney P, Selby S et al. (2004). Fatal acute lymphoblastic leukemia in mice transgenic for B cell-restricted bcl-xL and c-myc. J Immunol 172: 6684–6691.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Swanson-Mungerson MA, Caldwell RG, Bultema R, Longnecker R . (2005). 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.

    Article  CAS  Google Scholar 

  • Tao Q, Robertson KD, Manns A, Hildesheim A, Ambinder RF . (1998). Epstein–Barr virus (EBV) in endemic Burkitt's lymphoma: molecular analysis of primary tumor tissue. Blood 91: 1373–1381.

    CAS  PubMed  Google Scholar 

  • Taub R, Kirsch I, Morton C, Lenoir G, Swan D, Tronick S et al. (1982). Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci USA 79: 7837–7841.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Vervoorts J, Luscher-Firzlaff J, Luscher B . (2006). The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem 281: 34725–34729.

    Article  CAS  Google Scholar 

  • Wang H, Nicholas MW, Conway KL, Sen P, Diz R, Tisch RM et al. (2006). EBV latent membrane protein 2A induces autoreactive B cell activation and TLR hypersensitivity. J Immunol 177: 2793–2802.

    Article  CAS  Google Scholar 

  • Youle RJ, Strasser A . (2008). The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9: 47–59.

    Article  CAS  Google Scholar 

  • Zhu D, Qi CF, Morse III HC, Janz S, Stevenson FK . (2005). Deregulated expression of the Myc cellular oncogene drives development of mouse ‘Burkitt-like’ lymphomas from naive B cells. Blood 105: 2135–2137.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

RL is a John Edward Porter Professor in Biomedical Research and supported by the Public Health Service Grants CA62234 and CA73507 from the NCI. The authors thank Dr Herbert C Morse III, the NIAID, and the NCI for the λ-MYC transgenic mice.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    R Bultema, R Longnecker & M Swanson-Mungerson

Authors
  1. R Bultema
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Longnecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Swanson-Mungerson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Longnecker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bultema, R., Longnecker, R. & Swanson-Mungerson, M. Epstein–Barr virus LMP2A accelerates MYC-induced lymphomagenesis. Oncogene 28, 1471–1476 (2009). https://doi.org/10.1038/onc.2008.492

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.492

Keywords

Search

Advanced search

Quick links