CPG METHYLATION OF THE MAJOR EPSTEIN-BARR-VIRUS LATENCY PROMOTER IN BURKITTS-LYMPHOMA AND HODGKINS-DISEASE

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 lympho ma and in EBV-associated Hodgkin's disease. The failure to express the se proteins is almost certainly an important factor in the evasion of immunosurveillance by EBV-associated tumors. In a previous study, we h ave shown that transcriptional activation of the C promoter is inhibit ed by methylation of a particular CpG site upstream of the promoter th at prevents binding of a cellular protein (CBF2), and we have shown th at 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 bi nding region are predominantly methylated in African Burkitt's lymphom a 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 met hylation in the CBF2 binding region in a case of reversible EBV-associ ated B-cell lymphoma arising in an immunocompromised patient whose tum or shows C promoter transcriptional activity. By inhibiting expression of highly antigenic viral proteins, methylation of transcriptional co ntrol sequences may veil the presence of virus in tumor tissue from CD 8(+) cytotoxic T-cell immune surveillance and thus facilitate viral tu morigenesis. (C) 1996 by The American Society of Hematology.