title: BHRF1, the Epstein-Barr virus (EBV) homologue of the BCL-2 protooncogene, is transcribed in EBV-associated B-cell lymphomas and in reactive lymphocytes.
abstract: BHRF1, one of many Epstein-Barr virus (EBV)-encoded proteins, shows strong functional homology to the human bcl-2 proto-oncogene product, a protein involved in the pathogenesis of a subset of B-cell lymphomas, ie, follicle center cell lymphomas (FCCL). We have investigated the presence of possible latent and lytic transcripts of BHRF1 using a reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay in a group of EBV-associated B-cell lymphomas in patients with (N = 5) or without overt immunodeficiency (N = 4), in T-cell lymphomas (N = 9), and in cases of Hodgkin's disease (N = 6). BHRF1 transcription was found consistently in EBV-associated (ie, diffuse EBER 1/2-positive) B-cell lymphomas in patients with or without immune deficiency, whereas in EBV-associated T-cell lymphomas or in EBV-associated Hodgkin's disease, BHRF1 transcription was only detected in two T-cell lymphomas and one case of Hodgkin's disease, which also harbored EBER 1/2-positive reactive cells. Moreover, weak BHRF1 signals were found in two T-cell lymphomas where EBER 1/2 expression was detected mainly in sporadic reactive lymphocytes and in one reactive tonsil with sporadic EBER 1/2-positive lymphocytes. BHRF1 transcripts were found to be generated by the C or W promoter (associated with viral latency) and/or by the H promoter (associated with the virus lytic cycle). In all cases with H promoter-derived BHRF1 transcripts, transcripts encoding ZEBRA were also detected, suggesting a reactivation of the virus lytic cycle. Analysis of other EBV genes revealed transcription of BARFO in all tested EBV-harboring tissues. Transcription of EBNA1 and LMP1 was usually detected, whereas EBNA2 transcription was found exclusively in B-cell lymphomas in immunocompromised patients. These data demonstrate that BHRF1 transcripts are exclusively found in EBV-associated B-cell lymphomas. When BHRF1 transcripts are detected in T-cell lymphomas or in Hodgkin's disease, it is probably due to the presence of reactive EBER 1/2-positive lymphocytes. The consistent transcription of BHRF1 in EBV-associated B-cell lymphomas suggests a possible pathogenic role for this gene product in EBV-positive B-cell lymphomas analogous to bcl-2.
authors.affiliation: Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Oudejans
authors.forename: A J
authors.initials: AJ
authors.lastname: van den Brule
authors.forename: N M
authors.initials: NM
authors.lastname: Jiwa
authors.forename: P C
authors.initials: PC
authors.lastname: de Bruin
authors.forename: G J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: P
authors.initials: P
authors.lastname: van der Valk
authors.forename: J M
authors.initials: JM
authors.lastname: Walboomers
authors.forename: C J
authors.initials: CJ
authors.lastname: Meijer
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000378:metabolism*; D006689:Hodgkin Disease / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000032:analysis / Q000096:biosynthesis*
chemical_list: C083278:BHRF1 protein, Human herpesvirus 4; D017931:DNA Primers; C000715470:MAS1 protein, human; D015345:Oligonucleotide Probes; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins; D011505:Protein-Tyrosine Kinases