Transcriptional Profiling of Epstein-Barr Virus (EBV) Genes and Host Cellular Genes in Nasal NK/T-Cell Lymphoma and Chronic Active EBV Infection.

Abstract

Nasal NK/T-cell lymphoma is a uniquely aggressive and incurable subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein-Barr virus (EBV). Since necrosis is the common feature of nasal NK/T-cell lymphoma, the biological features of lymphoma cell are poorly understood because of the difficulty in obtaining sufficient viable specimens. The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. Although the molecular biology of EBV and B cell transformation has been extensively studied for years, little is known about the host-virus interaction in EBV-related NK- and T-cell malignancies. This study aimed to investigate the virus-host interaction in two types of EBV-associated NK/T-cell LPD which may clarify the possible association between infection and cancer. We attempted transcriptional profiling of EBV genes using a novel viral DNA microarray, HHV-4 Viruchip®, in addition to host cellular gene expression profiling using human oligonucleotide DNA microarrays, seeking to evaluate the possible role of EBV-host interaction in nasal NK/T-cell lymphoma and CAEBV infection. We used six cell lines with EBV-associated T/NK-cell LPD: SNK-1, SNK-6 and SNT-8 were isolated from nasal NK/T-cell lymphoma, and SNK-10, SNT-13 and SNT-16 were isolated from the peripheral blood of patients with CAEBV infection (Zhang Yu, et al., Br. J. Haematol. , 121: 805–814, 2003). We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was preferentially high in cell lines from CAEBV infection. We also analyzed the gene expression patterns of host cellular genes using a pathway-focused human oligonucleotide DNA microarray (NCBI GEO accession number: GPL1919 and GPL 1920). We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD, and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD.