CpG Methylation of the Major Epstein-Barr Virus Latency Promoter in Burkitt's Lymphoma and Hodgkin's Disease

• Published in: Blood Vol. 88; no. 8; pp. 3129 - 3136
• Main Authors: Robertson, K.D., Manns, A., Swinnen, L.J., Zong, J.C., Gulley, M.L., Ambinder, R.F.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.10.1996; The Americain Society of Hematology
• Subjects: 5-Methylcytosine; Anemia, Aplastic - complications; Biological and medical sciences; Burkitt Lymphoma - genetics; Burkitt Lymphoma - immunology; Burkitt Lymphoma - virology; CpG Islands; Cytosine - analogs & derivatives; Cytosine - analysis; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; DNA, Viral - chemistry; DNA, Viral - genetics; DNA-Binding Proteins - metabolism; Epstein-Barr Virus Nuclear Antigens - biosynthesis; Epstein-Barr Virus Nuclear Antigens - genetics; Epstein-Barr Virus Nuclear Antigens - immunology; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Ghana; Hematologic and hematopoietic diseases; Herpesviridae Infections - complications; Herpesviridae Infections - genetics; Herpesviridae Infections - virology; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - physiology; Hodgkin Disease - genetics; Hodgkin Disease - immunology; Hodgkin Disease - virology; Immunocompromised Host; Immunodominant Epitopes - biosynthesis; Immunodominant Epitopes - genetics; Immunodominant Epitopes - immunology; Immunologic Surveillance; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - complications; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - virology; Medical sciences; Methylation; Neoplasm Proteins - metabolism; Promoter Regions, Genetic; Tumor Virus Infections - complications; Tumor Virus Infections - genetics; Tumor Virus Infections - virology; Virus Latency - genetics; Gammaherpesvirinae; Nucleotide sequence; Herpesviridae; Burkitt lymphoma; Hodgkin disease; Malignant hemopathy; Epstein Barr virus; Non Hodgkin lymphoma; Gene expression; Lymphoma; Immunity; Infection; Virus; Antigen; Proteins; Lymphoproliferative syndrome; Viral disease; Inhibition; Molecular biology; Methylation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V88.8.3129.bloodjournal8883129

The Epstein-Barr virus (EBV) latency C promoter drives expression of a family of viral proteins commonly targeted by CD8 cytotoxic T cells. These proteins are not generally expressed in African Burkitt's lymphoma and in EBV-associated Hodgkin's disease. The failure to express these proteins is almost certainly an important factor in the evasion of immunosurveillance by EBV-associated tumors. In a previous study, we have shown that transcriptional activation of the C promoter is inhibited by methylation of a particular CpG site upstream of the promoter that prevents binding of a cellular protein (CBF2), and we have shown that this and adjacent CpG sites are methylated in a Burkitt's lymphoma cell line. In the present study, we show that CpG sites in the CBF2 binding region are predominantly methylated in African Burkitt's lymphoma and in EBV-associated Hodgkin's disease. In addition, we present the first direct evidence that the C promoter is transcriptionally silent in Burkitt's lymphoma. In contrast, we show a complete absence of methylation in the CBF2 binding region in a case of reversible EBV-associated B-cell lymphoma arising in an immunocompromised patient whose tumor shows C promoter transcriptional activity. By inhibiting expression of highly antigenic viral proteins, methylation of transcriptional control sequences may veil the presence of virus in tumor tissue from CD8(+) cytotoxic T-cell immune surveillance and thus facilitate viral tumorigenesis.