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Journal of Virology, May 2009, p. 5014-5027, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02264-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

c-Myc and Rel/NF-{kappa}B Are the Two Master Transcriptional Systems Activated in the Latency III Program of Epstein-Barr Virus-Immortalized B Cells {triangledown} ,{dagger}

Nathalie Faumont,1 Stéphanie Durand-Panteix,1 Martin Schlee,2,3 Sebastian Grömminger,2 Marino Schuhmacher,4,{ddagger} Michael Hölzel,2 Gerhard Laux,2 Reinhard Mailhammer,2 Andreas Rosenwald,5 Louis M. Staudt,6 Georg W. Bornkamm,2,§ and Jean Feuillard1,§*

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6101, Centre Hospitalier Universitaire Dupuytren, Université de Limoges, Laboratoire d'Hématologie, 2 rue du Docteur Marcland, 87025 Limoges, France,1 Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany,2 Institute of Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany,3 GPC Biotech AG, 82152 Martinsried, Germany,4 Institute of Pathology, University of Würzburg, Würzburg, Germany,5 Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208926

Received 29 October 2008/ Accepted 17 February 2009

The Epstein-Barr virus (EBV) latency III program imposed by EBNA2 and LMP1 is directly responsible for immortalization of B cells in vitro and is thought to mediate most immunodeficiency-related posttransplant lymphoproliferative diseases in vivo. To answer the question whether and how this proliferation program is related to c-Myc, we have established the transcriptome of both c-Myc and EBV latency III proliferation programs using a Lymphochip specialized microarray. In addition to EBV-positive latency I Burkitt lymphoma lines and lymphoblastoid cell lines (LCLs), we used an LCL expressing an estrogen-regulatable EBNA2 fusion protein (EREB2-5) and derivative B-cell lines expressing a constitutively active or tetracycline-regulatable c-myc gene. A total of 897 genes were found to be fourfold or more up- or downregulated in either one or both proliferation programs compared to the expression profile of resting EREB2-5 cells. A total of 661 (74%) of these were regulated similarly in both programs. Numerous repressed genes were known targets of STAT1, and most induced genes were known to be upregulated by c-Myc and to be involved in cell proliferation. In keeping with the gene expression patterns, inactivation of c-Myc by a chemical inhibitor or by conditional expression of dominant-negative c-Myc and Max mutants led to proliferation arrest of LCLs. Most genes differently regulated in both proliferation programs corresponded to genes induced by NF-{kappa}B in LCLs, and many of them coded for immunoregulatory and/or antiapoptotic molecules. Thus, c-Myc and NF-{kappa}B are the two main transcription factors responsible for the phenotype, growth pattern, and biological properties of cells driven into proliferation by EBV.

* Corresponding author. Mailing address: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6101, Centre Hospitalier Universitaire Dupuytren, Université de Limoges, Laboratoire d'Hématologie, 87025 Limoges, France. Phone: 33 5 55 05 67 40. Fax: 33 5 55 43 58 97. E-mail: jean.feuillard{at}unilim.fr

{triangledown} Published ahead of print on 4 March 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: Antisense Pharma GmbH, 93053 Regensburg, Germany.

§ G.W.B. and J.F. contributed equally to this work and are senior coauthors.

Journal of Virology, May 2009, p. 5014-5027, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02264-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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