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c-Myc overexpression promotes a germinal center-like program in Burkitt's lymphoma

Oncogene volume 29, pages 888–897 (2010)Cite this article

Abstract

The germinal center (GC) reaction has a pivotal function in human B-cell lymphomagenesis. Genetic aberrations occurring during somatic hypermutation and class switch recombination deregulate key factors controlling B-cell physiology and proliferation. Several human lymphoma entities are characterized by a constitutive GC phenotype and ongoing somatic hypermutation, but the molecular basis for this phenomenon is only partly understood. We have investigated the reasons for a constitutive GC-like program in Burkitt's lymphoma cells. Here, overexpression of c-Myc leads to a centroblast phenotype, promotes high constitutive expression of the key GC factors Bcl-6, E2A and activation-induced cytidine deaminase and contributes to proliferation and somatic hypermutation. Our findings elucidate how the activity of a pivotal transcription factor may freeze B-cell lymphoma cells in a constitutive GC-like state that is even maintained at an extrafollicular location.

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References

  • Adams JM, Gerondakis S, Webb E, Corcoran LM, Cory S . (1983). Cellular myc oncogene is altered by chromosome translocation to an immunoglobulin locus in murine plasmacytomas and is rearranged similarly in human Burkitt lymphomas. Proc Natl Acad Sci USA 80: 1982–1986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S et al. (1985). The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318: 533–538.

    Article  CAS  PubMed  Google Scholar 

  • Aiello A, Delia D, Fontanella E, Giardini R, Rilke F, Della Porta G . (1990). Expression of differentiation and adhesion molecules in sporadic Burkitt's lymphoma. Hematol Oncol 8: 229–238.

    Article  CAS  PubMed  Google Scholar 

  • Bachl J, Olsson C . (1999). Hypermutation targets a green fluorescent protein-encoding transgene in the presence of immunoglobulin enhancers. Eur J Immunol 29: 1383–1389.

    Article  CAS  PubMed  Google Scholar 

  • Cattoretti G, Pasqualucci L, Ballon G, Tam W, Nandula SV, Shen Q et al. (2005). Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 7: 445–455.

    Article  CAS  PubMed  Google Scholar 

  • Chapman CJ, Wright D, Stevenson FK . (1998). Insight into Burkitt's lymphoma from immunoglobulin variable region gene analysis. Leuk Lymphoma 30: 257–267.

    Article  CAS  PubMed  Google Scholar 

  • Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann R et al. (2008). AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 13: 167–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cole MD, Cowling VH . (2008). Transcription-independent functions of MYC: regulation of translation and DNA replication. Nat Rev Mol Cell Biol 9: 810–815.

    Article  CAS  PubMed  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  PubMed  PubMed Central  Google Scholar 

  • Dedeoglu F, Horwitz B, Chaudhuri J, Alt FW, Geha RS . (2004). Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkappaB. Int Immunol 16: 395–404.

    Article  CAS  PubMed  Google Scholar 

  • Di Noia JM, Neuberger MS . (2007). Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem 76: 1–22.

    Article  CAS  PubMed  Google Scholar 

  • Faili A, Aoufouchi S, Gueranger Q, Zober C, Leon A, Bertocci B et al. (2002). AID-dependent somatic hypermutation occurs as a DNA single-strand event in the BL2 cell line. Nat Immunol 3: 815–821.

    Article  CAS  PubMed  Google Scholar 

  • Gavioli R, Frisan T, Vertuani S, Bornkamm GW, Masucci MG . (2001). c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells. Nat Cell Biol 3: 283–288.

    Article  CAS  PubMed  Google Scholar 

  • Honjo T, Kinoshita K, Muramatsu M . (2002). Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol 20: 165–196.

    Article  CAS  PubMed  Google Scholar 

  • Johnston JM, Yu MT, Carroll WL . (1991). c-myc hypermutation is ongoing in endemic, but not all Burkitt's lymphoma. Blood 78: 2419–2425.

    CAS  PubMed  Google Scholar 

  • Khuda SE, Loo WM, Janz S, Van Ness B, Erickson LD . (2008). Deregulation of c-Myc confers distinct survival requirements for memory B cells, plasma cells, and their progenitors. J Immunol 181: 7537–7549.

    Article  CAS  PubMed  Google Scholar 

  • Klein U, Goossens T, Fischer M, Kanzler H, Braeuninger A, Rajewsky K et al. (1998). Somatic hypermutation in normal and transformed human B cells. Immunol Rev 162: 261–280.

    Article  CAS  PubMed  Google Scholar 

  • Klein U, Klein G, Ehlin-Henriksson B, Rajewsky K, Kuppers R . (1995). Burkitt's lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes. Mol Med 1: 495–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein U, Tu Y, Stolovitzky GA, Keller JL, Haddad Jr J, Miljkovic V et al. (2003). Transcriptional analysis of the B cell germinal center reaction. Proc Natl Acad Sci USA 100: 2639–2644.

    Article  CAS  PubMed  PubMed Central  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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kuppers R, Klein U, Hansmann ML, Rajewsky K . (1999). Cellular origin of human B-cell lymphomas. N Engl J Med 341: 1520–1529.

    Article  CAS  PubMed  Google Scholar 

  • Lee SC, Bottaro A, Chen L, Insel RA . (2006). Mad1 is a transcriptional repressor of Bcl-6. Mol Immunol 43: 1965–1971.

    Article  CAS  PubMed  Google Scholar 

  • Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH et al. (2008). Two levels of protection for the B cell genome during somatic hypermutation. Nature 451: 841–845.

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Valdez H, Guret C, de Bouteiller O, Fugier I, Banchereau J, Liu YJ . (1996). Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, P53, and Bax but not the survival gene bcl-2. J Exp Med 183: 971–977.

    Article  CAS  PubMed  Google Scholar 

  • Mierau M, Drexler GA, Kutzera A, Braunschmidt K, Ellwart J, Eckardt-Schupp F et al. (2008). Non-conservative homologous recombination in human B lymphocytes is promoted by activation-induced cytidine deaminase and transcription. Nucleic Acids Res 36: 5591–5601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niu H, Ye BH, Dalla-Favera R . (1998). Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev 12: 1953–1961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pajic A, Staege MS, Dudziak D, Schuhmacher M, Spitkovsky D, Eissner G et al. (2001). Antagonistic effects of c-myc and Epstein-Barr virus latent genes on the phenotype of human B cells. Int J Cancer 93: 810–816.

    Article  CAS  PubMed  Google Scholar 

  • Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti RS, Dalla-Favera R . (2003). Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101: 2914–2923.

    Article  CAS  PubMed  Google Scholar 

  • Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L et al. (1998). BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci USA 95: 11816–11821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R et al. (2001). Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412: 341–346.

    Article  CAS  PubMed  Google Scholar 

  • Polack A, Feederle R, Klobeck G, Hortnagel K . (1993). Regulatory elements in the immunoglobulin kappa locus induce c-myc activation and the promoter shift in Burkitt's lymphoma cells. EMBO J 12: 3913–3920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Polack A, Hortnagel K, Pajic A, Christoph B, Baier B, Falk M et al. (1996). c-myc activation renders proliferation of Epstein-Barr virus (EBV)-transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1. Proc Natl Acad Sci USA 93: 10411–10416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajewsky K . (1996). Clonal selection and learning in the antibody system. Nature 381: 751–758.

    Article  CAS  PubMed  Google Scholar 

  • Refaeli Y, Young RM, Turner BC, Duda J, Field KA, Bishop JM . (2008). The B cell antigen receptor and overexpression of MYC can cooperate in the genesis of B cell lymphomas. PLoS Biol 6: e152.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ruckerl F, Busse B, Bachl J . (2006). Episomal vectors to monitor and induce somatic hypermutation in human Burkitt-Lymphoma cell lines. Mol Immunol 43: 1645–1652.

    Article  PubMed  Google Scholar 

  • Rutherford MN, LeBrun DP . (1998). Restricted expression of E2A protein in primary human tissues correlates with proliferation and differentiation. Am J Pathol 153: 165–173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, Bhagat G et al. (2007). A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12: 280–292.

    Article  CAS  PubMed  Google Scholar 

  • Sayegh CE, Quong MW, Agata Y, Murre C . (2003). E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nat Immunol 4: 586–593.

    Article  CAS  PubMed  Google Scholar 

  • Schoetz U, Cervelli M, Wang YD, Fiedler P, Buerstedde JM . (2006). E2A expression stimulates Ig hypermutation. J Immunol 177: 395–400.

    Article  CAS  PubMed  Google Scholar 

  • Schuhmacher M, Kohlhuber F, Holzel M, Kaiser C, Burtscher H, Jarsch M et al. (2001). The transcriptional program of a human B cell line in response to Myc. Nucleic Acids Res 29: 397–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaffer AL, Rosenwald A, Hurt EM, Giltnane JM, Lam LT, Pickeral OK et al. (2001). Signatures of the immune response. Immunity 15: 375–385.

    Article  CAS  PubMed  Google Scholar 

  • Shen HM, Peters A, Baron B, Zhu X, Storb U . (1998). Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280: 1750–1752.

    Article  CAS  PubMed  Google Scholar 

  • Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R et al. (2008). MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 28: 621–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thorley-Lawson DA, Allday MJ . (2008). The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nat Rev Microbiol 6: 913–924.

    Article  CAS  PubMed  Google Scholar 

  • Toyama H, Okada S, Hatano M, Takahashi Y, Takeda N, Ichii H et al. (2002). Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity 17: 329–339.

    Article  CAS  PubMed  Google Scholar 

  • Wagner SD, Amen F, Trivedi PS, Horncastle D, Elderfield K, Naresh KN . (2007). Bcl-6 and c-Myc are rarely co-expressed in adult diffuse large B-cell lymphoma. Leuk Lymphoma 48: 1510–1513.

    Article  CAS  PubMed  Google Scholar 

  • Wang CL, Wabl M . (2005). Hypermutation rate normalized by chronological time. J Immunol 174: 5650–5654.

    Article  CAS  PubMed  Google Scholar 

  • Yin X, Giap C, Lazo JS, Prochownik EV . (2003). Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene 22: 6151–6159.

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa K, Okazaki IM, Eto T, Kinoshita K, Muramatsu M, Nagaoka H et al. (2002). AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296: 2033–2036.

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Bardwell PD, Woo CJ, Poltoratsky V, Scharff MD, Martin A . (2001). Clonal instability of V region hypermutation in the Ramos Burkitt's lymphoma cell line. Int Immunol 13: 1175–1184.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Sabine Fischer-Burkart for expert technical assistance, Torsten Thiel for contributions to the RNAi system, Maren Mierau and Dirk Eick for discussion and support, and Ursula Zimber-Strobl, Georg Bornkamm and Ralf Küppers for critical reading of the manuscript. This work was supported by grants from the German José Carreras Leukemia Foundation (SP/03/10 and R05/10v), the Wilhelm Sander foundation (2003.046.2) and the Deutsche Forschungsgemeinschaft (TRR54-TPA4).

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  1. Institute of Clinical Molecular Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany

    H Scheller, S Tobollik, A Kutzera, M Eder, J Unterlehberg, I Pfeil & B Jungnickel

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  1. H Scheller
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  2. S Tobollik
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Correspondence to B Jungnickel.

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Scheller, H., Tobollik, S., Kutzera, A. et al. c-Myc overexpression promotes a germinal center-like program in Burkitt's lymphoma. Oncogene 29, 888–897 (2010). https://doi.org/10.1038/onc.2009.377

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