Three Restricted Forms of Epstein-Barr Virus Latency Counteracting Apoptosis in C-Myc-Expressing Burkitt Lymphoma Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-10, Vol.103 (40), p.14935-14940
• Main Authors: Kelly, Gemma L., Milner, Anne E., Baldwin, Gouri S., Bell, Andrew I., Rickinson, Alan B.
• Format: Article
• Language: English
• Subjects: Antigens; Apoptosis; B lymphocytes; Biological Sciences; Burkitt Lymphoma - metabolism; Burkitt Lymphoma - pathology; Cancer; Cell growth; Cell Line, Tumor; Cell lines; Child; Chromosomes; Clone Cells; Epstein Barr virus infections; Epstein-Barr virus; Epstein-Barr Virus Nuclear Antigens - genetics; Epstein-Barr Virus Nuclear Antigens - metabolism; Female; Gene expression; Gene Expression Regulation, Viral; Genome, Viral - genetics; Genomes; Herpesvirus 4, Human - physiology; Human herpesvirus; Humans; Infections; Proto-Oncogene Proteins c-myc - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription, Genetic; Tumor cell line; Tumor Cells, Cultured; Tumors; Viral Matrix Proteins - metabolism; Viral Proteins - metabolism; Virus Latency - physiology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0509988103

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 EBNAI-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.