title: Different patterns of Epstein-Barr virus latency in endemic Burkitt lymphoma (BL) lead to distinct variants within the BL-associated gene expression signature.
abstract: Epstein-Barr virus (EBV) is present in all cases of endemic Burkitt lymphoma (BL) but in few European/North American sporadic BLs. Gene expression arrays of sporadic tumors have defined a consensus BL profile within which tumors are classifiable as "molecular BL" (mBL). Where endemic BLs fall relative to this profile remains unclear, since they not only carry EBV but also display one of two different forms of virus latency. Here, we use early-passage BL cell lines from different tumors, and BL subclones from a single tumor, to compare EBV-negative cells with EBV-positive cells displaying either classical latency I EBV infection (where EBNA1 is the only EBV antigen expressed from the wild-type EBV genome) or Wp-restricted latency (where an EBNA2 gene-deleted virus genome broadens antigen expression to include the EBNA3A, -3B, and -3C proteins and BHRF1). Expression arrays show that both types of endemic BL fall within the mBL classification. However, while EBV-negative and latency I BLs show overlapping profiles, Wp-restricted BLs form a distinct subgroup, characterized by a detectable downregulation of the germinal center (GC)-associated marker Bcl6 and upregulation of genes marking early plasmacytoid differentiation, notably IRF4 and BLIMP1. Importantly, these same changes can be induced in EBV-negative or latency I BL cells by infection with an EBNA2-knockout virus. Thus, we infer that the distinct gene profile of Wp-restricted BLs does not reflect differences in the identity of the tumor progenitor cell per se but differences imposed on a common progenitor by broadened EBV gene expression.
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Kelly
authors.forename: Julianna
authors.initials: J
authors.lastname: Stylianou
authors.forename: Jane
authors.initials: J
authors.lastname: Rasaiyaah
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomas
authors.forename: Deborah
authors.initials: D
authors.lastname: Croom-Carter
authors.forename: Christian
authors.initials: C
authors.lastname: Kohler
authors.forename: Rainer
authors.initials: R
authors.lastname: Spang
authors.forename: Ciaran
authors.initials: C
authors.lastname: Woodman
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Bell
mesh_terms: D000956:Antigens, Viral / Q000096:biosynthesis; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000821:virology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D019309:Epstein-Barr Virus Nuclear Antigens / Q000096:biosynthesis; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000145:classification / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000096:biosynthesis; D059467:Transcriptome; D015854:Up-Regulation; D014764:Viral Proteins / Q000096:biosynthesis; D017735:Virus Latency / Q000235:genetics*
chemical_list: D000956:Antigens, Viral; C084103:BCL6 protein, human; C083278:BHRF1 protein, Human herpesvirus 4; D004268:DNA-Binding Proteins; C402641:EBNA-2 protein, Human herpesvirus 4; C508151:EBNA-3A antigen; C422762:EBNA-3B antigen; C498774:EBNA-3C, epstein-barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D050835:Interferon Regulatory Factors; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D014764:Viral Proteins; C413486:viral interferon regulatory factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; C417029:EBV-encoded nuclear antigen 1