Molecular signature of Epstein Barr virus-positive Burkitt lymphoma and post-transplant lymphoproliferative disorder suggest different roles for Epstein Barr virus

Mohsen Navari,Lorenzo Leoncini,Fabio Fuligni,Davide Gibellini,Maria R Sapienza,Claudio Tripodo,Maria A Laginestra,Giulia De Falco,Pier P Piccaluga,Maura Rossi,Maryam Etebari,Maria R Ambrosio,Stefano A Pileri

doi:10.3389/fmicb.2014.00728

Abstract

Epstein Barr virus (EBV) infection is commonly associated with human cancer and, in particular, with lymphoid malignancies. Although the precise role of the virus in the pathogenesis of different lymphomas is largely unknown, it is well recognized that the expression of viral latent proteins and miRNA can contribute to its pathogenetic role. In this study, we compared the gene and miRNA expression profile of two EBV-associated aggressive B non-Hodgkin lymphomas known to be characterized by differential expression of the viral latent proteins aiming to dissect the possible different contribution of such proteins and EBV-encoded miRNAs. By applying extensive bioinformatic inferring and an experimental model, we found that EBV+ Burkitt lymphoma presented with significant over-expression of EBV-encoded miRNAs that were likely to contribute to its global molecular profile. On the other hand, EBV+ post-transplant diffuse large B-cell lymphomas presented a significant enrichment in genes regulated by the viral latent proteins. Based on these different viral and cellular gene expression patterns, a clear distinction between EBV+ Burkitt lymphoma and post-transplant diffuse large B-cell lymphomas was made. In this regard, the different viral and cellular expression patterns seemed to depend on each other, at least partially, and the latency type most probably played a significant role in their regulation. In conclusion, our data indicate that EBV influence over B-cell malignant clones may act through different mechanisms of transcriptional regulation and suggest that potentially different pathogenetic mechanisms may depend upon the conditions of the interaction between EBV and the host that finally determine the latency pattern.

Highlights

Epstein Barr Virus (EBV) is a human gamma-herpesvirus that normally infects 90–95% of the human normal population, and persists for life of its host
EBV-DEREGULATED GENES IN DIFFERENT EBV LATENCY TYPES MIGHT INTERFERE WITH RELEVANT BIOLOGICAL ACTIVITIES. As it appeared that EBV significantly affected, though in different ways, the global gene expression profile (GEP) of both BL and Post-Transplant Lymphoproliferative Disorder (PTLD)-diffuse large B-cell lymphoma (DLBCL), we investigated whether genes likely to be modulated by EBV were involved in specific biological functions, aiming to further appreciate its specific role in the pathobiology of these lymphomas
Latency type I is primarily observed in BL, where only one latent protein (EBNA-1), EBERs and BART microRNAs are expressed (Bellan et al, 2005; Piccaluga et al, 2011; Qiu et al, 2011)

Summary

Introduction

Epstein Barr Virus (EBV) is a human gamma-herpesvirus that normally infects 90–95% of the human normal population, and persists for life of its host. This virus was first discovered in endemic Burkitt Lymphoma (eBL), and was nominated as the first human tumor virus. The manifestation of EBV infection is not the same in all EBVrelated tumors, since the virus can adopt different gene expression programs for persistence, called latency types. In latency type I, which is the most limited expression pattern, EBNA-1 molecule is the only latent protein expressed (Gross, 2001; Piccaluga et al, 2011; Onnis et al, 2012)

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