Abstract

Background: Epstein-Barr virus (EBV) is an oncogenic virus found in about 95% of endemic Burkitt lymphoma (BL) cases. In latently infected cells, EBV DNA is mostly maintained in episomal form, but it can also be integrated into the host genome, or both forms can coexist in the infected cells. Methods: In this study, we mapped the chromosomal integration sites of EBV (EBV-IS) into the genome of 21 EBV+ BL cell lines (BL-CL) using metaphase fluorescence in situ hybridization (FISH). The data were used to investigate the EBV-IS distribution pattern in BL-CL, its relation to the genome instability, and to assess its association to common fragile sites and episomes. Results: We detected a total of 459 EBV-IS integrated into multiple genome localizations with a preference for gene-poor chromosomes. We did not observe any preferential affinity of EBV to integrate into common and rare fragile sites or enrichment of EBV-IS at the chromosomal breakpoints of the BL-CL analyzed here, as other DNA viruses do. Conclusions: We identified a non-random integration pattern into 13 cytobands, of which eight overlap with the EBV-IS in EBV-transformed lymphoblastoid cell lines and with a preference for gene- and CpGs-poor G-positive cytobands. Moreover, it has been demonstrated that the episomal form of EBV interacts in a non-random manner with gene-poor and AT-rich regions in EBV+ cell lines, which may explain the observed affinity for G-positive cytobands in the EBV integration process. Our results provide new insights into the patterns of EBV integration in BL-CL at the chromosomal level, revealing an unexpected connection between the episomal and integrated forms of EBV.

Highlights

  • Epstein-Barr virus (EBV), a human gamma-1 herpesvirus, is widespread worldwide and is carried as a latent asymptomatic infection in the vast majority of individuals

  • The presence of the EBV genome in Burkitt lymphoma (BL)-CLs was confirmed in all EBV+ BL cell lines (BL-CL) analyzed by PCR

  • Our data provide evidence for a dichotomous pattern of EBV integration in the BL-CL analyzed in our study

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Summary

Introduction

Epstein-Barr virus (EBV), a human gamma-1 herpesvirus, is widespread worldwide and is carried as a latent asymptomatic infection in the vast majority of individuals. EBV has a powerful growth-transforming ability in cells of epithelial and lymphoid origin and is etiologically linked to a range of lymphoproliferative lesions, malignant lymphomas, and carcinomas [1]. BL is a highly aggressive mature B-cell lymphoid neoplasia [2]. The hallmark of this disease is the overexpression of MYC, commonly resulting from the translocation t (8;14). The data were used to investigate the EBV-IS distribution pattern in BL-CL, its relation to the genome instability, and to assess its association to common fragile sites and episomes. We did not observe any preferential affinity of EBV to integrate into common and rare fragile sites or enrichment of EBV-IS at the chromosomal breakpoints of the BL-CL analyzed here, as other DNA viruses do.

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