Epstein–Barr virus infection leads to partial phenotypic reversion of terminally differentiated malignant B cells Eleni Anastasiadou a , Signe Vaeth b , Laura Cuomo c , Francesco Boccellato a , Sara Vincenti d , Mara Cirone a , Carlo Presutti d , Steffen Junker b , Gösta Winberg e , Luigi Frati a , Paul A. Wade f , Alberto Faggioni a , Pankaj Trivedi a, * a Istituto Pasteur-Fondazione Cenci-Bolognetti, Department of Experimental Medicine and Pathology, University of Rome ‘‘La Sapienza” Viale Regina Elena 324, 00161 Rome, Italy b Department of Human Genetics, Aarhus University, Aarhus, Denmark c Department of Clinical Pathology, San Filippo Neri Hospital, 00135 Rome, Italy d Department of Genetics and Molecular Biology, La Sapienza University, Via Dei Sardi, 70, 00185 Rome, Italy e MTC, Karolinska Institute, Stockholm, Sweden f Laboratory of Molecular Carcinogenesis, NIEHS Research Triangle Park, NC 27709, USA article info Article history: Received 19 November 2008 Received in revised form 3 April 2009 Accepted 16 April 2009 Keywords: EBV Latency Myeloma Differentiation abstract The B cell lymphomas associated with Epstein–Barr virus (EBV) are not limited to any spe- cific stage of B cell differentiation but covers widely different B cell phenotypes. In vitro infection of the virus negative tumors with a recombinant EBV strain has provided impor- tant insights into virus–tumor interaction. Here, we investigated the interaction between EBV and terminally differentiated tumor derived B cells, namely multiple myeloma (MM). The in vitro EBV infected MM expressed restricted viral latency. Acquisition of the virus was accompanied by a partial reprogramming to a mature B cell phenotype. Thus, the plasma cell markers syndecan-1 (CD138), Blimp1 and MUM1 were downregulated, while expression of HLADR, CIITA and TCL1, which are normally not expressed in plasma- cytoid cells, was upregulated. The silenced transcription factor gene encoding Pax5 and its target BLNK were activated. Significantly, the free lambda light chains secreted in the med- ium were reduced in EBV infected MM clones. Collectively, these results suggest that the restricted EBV latency can cause at least partial phenotypic reversion of terminally differ- entiated B tumor cells. We suggest that the restricted EBV latent gene expression may not only be the consequence but the cause of the mature B cell phenotype, actively participat- ing in the virus persistence. Ó 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Epstein–Barr virus (EBV) is the most transforming hu- man virus known for B lymphocytes. More than 90% of the human population is infected with EBV and the virus remains latent in memory B cells [1]. In vitro infection of peripheral blood derived B cells lead to permanently grow- ing cell lines called lymphoblastoid cell lines (LCLs). In spite of the high transformation capacity of this virus for B cells in vitro, most healthy seropositive individuals carry it for life-time without negative repercussions. This harmonic host-parasite equilibrium is believed to be due to lack of expression of immunogenic viral proteins and a tight host immunesurveillance of the virally infected cells [1]. EBV is also consistently associated with a wide variety of malignant tumors, such as Burkitt’s lymphoma (BL), nasopharyngeal carcinoma (NPC), Hodgkin’s disease (HD) 0304-3835/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2009.04.025 * Corresponding author. Tel.: +39 06 49973015; fax: +39 06 4454820. E-mail addresses: alberto.faggioni@uniroma1.it (A. Faggioni), Pankaj. Trivedi@uniroma1.it (P. Trivedi). Cancer Letters 284 (2009) 165–174 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet