Three restricted forms of Epstein-Barr virus latency counteracting apoptosis in c-myc-expressing Burkitt lymphoma cells.
Epstein-Barr virus (EBV), a human herpesvirus, transforms B cell growth in vitro through expressing six virus-coded Epstein-Barr nuclear antigens (EBNAs) and two latent membrane proteins (LMPs). In many EBV-associated tumors, however, viral antigen expression is more restricted, and the aetiological role of the virus is unclear. For example, endemic Burkitt lymphoma (BL) classically presents as a monoclonal, c-myc-translocation-positive tumor in which every cell carries EBV as an EBNA1-only (Latency I) infection; such homogeneity among EBV-positive cells, and the lack of EBV-negative comparators, hampers attempts to understand EBV's role in BL pathogenesis. Here, we describe an endemic BL that was unusually heterogeneous at the single-cell level and, in early passage culture, yielded a range of cellular clones, all with the same c-myc translocation but differing in EBV status. Rare EBV-negative cells were isolated alongside EBV-positive cells displaying one of three forms of restricted latency: (i) conventional Latency I expressing EBNA1 only from a WT virus genome, (ii) Wp-restricted latency expressing EBNAs 1, 3A, 3B, 3C, and -LP only from an EBNA2-deleted genome, and (iii) a previously undescribed EBNA2(+)/LMP1(-) latency in which all six EBNAs are expressed again in the absence of the LMPs. Interclonal comparisons showed that each form of EBV infection was associated with a specific degree of protection from apoptosis. Our work suggests that EBV acts as an antiapoptotic rather than a growth-promoting agent in BL by selecting among three transcriptional programs, all of which, unlike the full virus growth-transforming program, remain compatible with high c-myc expression.
Kelly
Gemma L
GL
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Milner
Anne E
AE
Baldwin
Gouri S
GS
Bell
Andrew I
AI
Rickinson
Alan B
AB
D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D002999:Clone Cells; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000378:metabolism; D005260:Female; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D017735:Virus Latency / Q000502:physiology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014763:Viral Matrix Proteins; D014764:Viral Proteins