CpG methylation of the major Epstein-Barr virus latency promoter in Burkitt's lymphoma and Hodgkin's 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 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.
Robertson
K D
KD
Department of Oncology, Johns Hopkins University School of Medicine Baltimore, MD, USA.
Manns
A
A
Swinnen
L J
LJ
Zong
J C
JC
Gulley
M L
ML
Ambinder
R F
RF
D044503:5-Methylcytosine; D000741:Anemia, Aplastic / Q000150:complications; D002051:Burkitt Lymphoma / Q000235:genetics / Q000276:immunology / Q000821:virology*; D018899:CpG Islands; D003596:Cytosine / Q000031:analogs & derivatives* / Q000032:analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000235:genetics; D004279:DNA, Viral / Q000737:chemistry* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D019309:Epstein-Barr Virus Nuclear Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005869:Ghana; D006566:Herpesviridae Infections / Q000150:complications / Q000235:genetics / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000502:physiology; D006689:Hodgkin Disease / Q000235:genetics / Q000276:immunology / Q000821:virology*; D016867:Immunocompromised Host; D016056:Immunodominant Epitopes / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007157:Immunologic Surveillance; D016393:Lymphoma, B-Cell / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000821:virology*; D008745:Methylation; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014412:Tumor Virus Infections / Q000150:complications / Q000235:genetics / Q000821:virology*; D017735:Virus Latency / Q000235:genetics*
D004273:DNA, Neoplasm; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; D016056:Immunodominant Epitopes; D009363:Neoplasm Proteins; D044503:5-Methylcytosine; D003596:Cytosine; D004248:DNA (Cytosine-5-)-Methyltransferases