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Review
. 2014 Dec;33(12):609-19.
doi: 10.5732/cjc.014.10190. Epub 2014 Nov 21.

Epstein-Barr virus and Burkitt lymphoma

Martin Rowe  1 , Leah Fitzsimmons, Andrew I Bell
Affiliations
Review

Epstein-Barr virus and Burkitt lymphoma

Martin Rowe et al. Chin J Cancer. 2014 Dec.

Abstract

In 1964, a new herpesvirus, Epstein-Barr virus (EBV), was discovered in cultured tumor cells derived from a Burkitt lymphoma (BL) biopsy taken from an African patient. This was a momentous event that reinvigorated research into viruses as a possible cause of human cancers. Subsequent studies demonstrated that EBV was a potent growth-transforming agent for primary B cells, and that all cases of BL carried characteristic chromosomal translocations resulting in constitutive activation of the c-MYC oncogene. These results hinted at simple oncogenic mechanisms that would make Burkitt lymphoma paradigmatic for cancers with viral etiology. In reality, the pathogenesis of this tumor is rather complicated with regard to both the contribution of the virus and the involvement of cellular oncogenes. Here, we review the current understanding of the roles of EBV and c-MYC in the pathogenesis of BL and the implications for new therapeutic strategies to treat this lymphoma.

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Figures

Figure 1.
Figure 1.. Epstein-Barr virus (EBV) gene expression in Burkitt lymphoma.
A, organization of the viral genes express during latent, non-productive infection. The schematic is not to scale, and for simplicity the double-stranded DNA episomal viral genome is represented here as a linear genome. The 6 nuclear protein-encoding genes (EBNAs; in red) and the latent membrane protein-2A and -2B genes (LMP2A/B; in blue) are transcribed in a rightward direction. The latent membrane protein-1 gene (LMP1; in blue) is transcribed from the reverse DNA strand. The relative locations of the non-coding RNAs, which include the EBV-encoded non-polyadenylated RNAs (EBERs) and numerous microRNAs, are depicted in purple. The origin of plasmid replication (OriP), which contains dyad repeat and direct repeat elements, is indicated downstream of the EBER gene. For reference, the terminal repeat (TR) region is indicated. The TRs are the site of genome linearization during lytic virus replication and re-ligation following latent infection. Because the first coding exon of LMP2A (and the first non-coding exon of LMP2B) is located to the left of the TR and the common LMP2A/B-coding exons are located to the right of the TR, transcription of LMP2A from the TP1 promoter and LMP2B from the TP2 promoter can only occur from the episomal genome. B, different latent gene transcription patterns. All of the coding and non-coding latent genes are expressed in normal B cells that are directly growth-transformed by EBV. This form of latency (Latency III) is observed in lymphoblastoid cell lines (LCLs) in vitro and in post-transplantation lymphoproliferative disease in vivo. All 6 EBNAs and BHRF1 vBCL2 are transcribed from the Wp and/or Cp promoters during Latency III. The majority of EBV-positive Burkitt lymphoma tumor biopsies display a Latency I pattern of gene expression in which the non-coding RNAs are expressed, but EBNA1 is the only protein-encoding gene transcribed. EBNA1 gene transcription in Latency I is driven from the Qp promoter (in contrast to Latency III in which Cp/Wp-driven transcription occurs). A minority of Burkitt lymphomas carry genomes with a deletion spanning their EBNA2 gene, from which they display a Wp-restricted form of latency. Wp-driven transcription allows expression of all of the remaining 5 EBNAs and also of BHRF1, which is expressed at much higher levels than in Latency III LCLs. The absence of EBNA2 in Wp-restricted latency results in repression of EBNA2-dependent LMP1 and LMP2 gene expression.
Figure 2.
Figure 2.. Cellular gene mutations in Burkitt lymphoma.
Key proliferative and apoptotic pathways induced by c-MYC are indicated in this schematic adapted from Schmitz et al. and Kelly & Rickinson. Genes that are frequently mutated in Burkitt lymphoma are indicated. Green asterisks denote gene- activating mutations, while red asterisks denote inhibitory mutations.
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