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Epstein-Barr virus microRNAs repress BCL6 expression in diffuse large B-cell lymphoma

Leukemia volume 26, pages 180–183 (2012)Cite this article

We have studied the miRNA expression profile in 36 DLBCL samples using miRNA microarrays. Prevalence of EBV in this series (33 EBV-negative and 3 EBV-positive) was close to normal prevalence in DLBCL.1 Twenty-two out of thirty-two analysed viral miRNAs were significantly upregulated in EBV-positive samples (>two-fold change; t-test corrected P-value<0.05, Figure 1c, Supplementary table 2 and Supplementary table 3). None of the miRNAs belonged to the BHRF1 cluster, a finding that confirms previous results suggesting that the highest levels of these miRNAs are reached during the lytic cycle.4 To test the hypothesis that some of these miRNAs can potentially downregulate BCL6, we made a bioinformatic prediction using the miRanda algorithm. This prediction indentified 21 binding sites in the 3′ UTR of BCL6 for 18 EBV-encoded miRNAs (Supplementary table 1). More than 70% of these predictions were also found with other algorithms (Supplementary Figure 1). Ten of these miRNAs were also differentially expressed between EBV-positive and EBV-negative DLBCL cases. This high proportion of miRNAs potentially targeting BCL6 suggests a physiological mechanism of the virus to reduce the amount of BCL6. Consequently, we selected four EBV-encoded miRNAs for further validation. These miRNAs were selected according to the following parameters: 1) attainment of a high score from miRanda and 2) differential expression in the EBV-positive DLBCL cases. In this way, we selected ebv-miR-BART3, ebv-miR-BART9 and ebv-miR-BART17-5p. We also selected ebv-miR-BART7 because, although it does not achieve one of the highest scores from miRanda, the program predicts two binding sites for the miRNA in the 3′ UTR of BCL6, increasing the probability of it being a bona fide regulator of BCL6 (Supplementary Figure 2). To analyse these miRNAs in a larger series of cases, we selected 40 cases (15 EBV-positive and 25 EBV-negative) from the 149-patients series to check their expression by RT–PCR. The mean of the viral miRNAs expression among EBER-positive patients was 10- to 100-fold higher compared with EBER-negative patients (Figure 1d). We also analysed EBV-encoded miRNA levels by RT–PCR in BL and DLBCL-derived cell lines and observed a correlation between BCL6 protein and miRNA levels (Figures 1e and f). These results indicate that a relatively low level of expression of these miRNAs could enable the high level of expression of BCL6 observed in EBV-positive BL,5 thus explaining the differences between BL and DLBCL.

EBV is more frequently found in tumors with a plasmablastic phenotype in which other factors (for example, expression of BLIMP1) could be repressing BCL6 at the transcriptional level.6 Our data support a role of EBV microRNAs that could help to diminish BCL6 expression facilitating BCL6 transcriptional repression by BCL6 targets such as BLIMP1.7 However, the reason by which EBV downregulates BCL6 in DLBCL remains unknown. It is known that several EBV-driven lymphomas rely on the activation of the NF-kB pathway8 as well as ABC-type DLBCL.9 Viral proteins such as LMP1 and LMP2A can activate the NF-κB pathway directly or indirectly to promote the survival of the host cell.8, 10, 11, 12 Because BCL6 represses NF-κB under normal and pathogenic conditions,2 BCL6 downregulation may be necessary to promote survival of the EBV-positive neoplastic cells in some DLBCLs. EBV does not repress BCL6 in Burkitt lymphoma; however, in this tumor type, activation of the NF-κB pathway has been shown to induce apoptosis,13 and so the role of the virus might be different in this disease.

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References

  1. Swerdlow SHCE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds). WHO Classification: Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2008.

    Google Scholar 

  2. Perez-Rosado A, Artiga M, Vargiu P, Sanchez-Aguilera A, Alvarez-Barrientos A, Piris M . BCL6 represses NFkappaB activity in diffuse large B-cell lymphomas. J Pathol 2008; 214: 498–507.

    Article  CAS  Google Scholar 

  3. Carbone A, Gaidano G, Gloghini A, Pastore C, Saglio G, Tirelli U et al. BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas: inverse relationship with Epstein-Barr virus-encoded latent membrane protein-1 expression. Am J Pathol 1997; 150: 155–165.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J et al. Identification of virus-encoded microRNAs. Science 2004; 304: 734–736.

    Article  CAS  Google Scholar 

  5. Ferry JA . Burkitt's lymphoma: clinicopathologic features and differential diagnosis. Oncologist 2006; 11: 375–383.

    Article  Google Scholar 

  6. Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, Rosenwald A et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 2002; 17: 51–62.

    Article  CAS  Google Scholar 

  7. Vasanwala FH, Kusam S, Toney LM, Dent AL . Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B lymphocyte differentiation by the B cell lymphoma-6 protooncogene. J Immunol 2002; 169: 1922–1929.

    Article  CAS  Google Scholar 

  8. Keller SA, Hernandez-Hopkins D, Vider J, Ponomarev V, Hyjek E, Schattner EJ et al. NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Blood 2006; 107: 3295–3302.

    Article  CAS  Google Scholar 

  9. Davis RE, Brown KD, Siebenlist U, Staudt LM . Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001; 194: 1861–1874.

    Article  CAS  Google Scholar 

  10. Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E . The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 1995; 80: 389–399.

    Article  CAS  Google Scholar 

  11. Cahir McFarland ED, Izumi KM, Mosialos G . Epstein-barr virus transformation: involvement of latent membrane protein 1-mediated activation of NF-kappaB. Oncogene 1999; 18: 6959–6964.

    Article  CAS  Google Scholar 

  12. Cahir-McFarland ED, Carter K, Rosenwald A, Giltnane JM, Henrickson SE, Staudt LM et al. Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells. J Virol 2004; 78: 4108–4119.

    Article  CAS  Google Scholar 

  13. Klapproth K, Sander S, Marinkovic D, Baumann B, Wirth T . The IKK2/NF-{appa}B pathway suppresses MYC-induced lymphomagenesis. Blood 2009; 114: 2448–2458.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to acknowledge all members of CNIOs Lymphoma Group for their thoughtful discussion. This study was funded with the following grants: from Ministerio de Educación y Ciencia, Spain SAF2007-65957-C02-02, SAF2008-03871; from the Fondo de Investigaciones Sanitarias, RTICC RD06/0020/0107 and PI10/00621; from Fundación Científica de la Asociación Española Contra el Cáncer (AECC). LDL is supported by a fellowship from Ministerio de Sanidad y Consumo (FI08/00038); NM is supported by a contract from Ministerio de Sanidad y Consumo (CP06/00002).

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  1. M Sánchez-Beato and M A Piris: Senior authors.

Authors and Affiliations

  1. Lymphoma Group, Molecular Pathology Programme,

    D Martín-Pérez, P Vargiu, S Montes-Moreno, S M Rodríguez-Pinilla, L D Lisio, N Martínez, M Sánchez-Beato & M A Piris

  2. Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    D Martín-Pérez, P Vargiu, S Montes-Moreno, S M Rodríguez-Pinilla, L D Lisio, N Martínez, M Sánchez-Beato & M A Piris

  3. Bioinformatics Unit (UBio), Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    E A León & D G Pisano

  4. Department of Pathology. Hospital Virgen de la Salud, Toledo, Spain

    R Rodríguez & M Mollejo

  5. Department of Pathology, Vall d’Hebron University Hospital, Barcelona, Spain

    J Castellvi

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Martín-Pérez, D., Vargiu, P., Montes-Moreno, S. et al. Epstein-Barr virus microRNAs repress BCL6 expression in diffuse large B-cell lymphoma. Leukemia 26, 180–183 (2012). https://doi.org/10.1038/leu.2011.189

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