title: A deletion mutant of the LMP1 oncogene of Epstein-Barr virus is associated with evolution of angioimmunoblastic lymphadenopathy into B immunoblastic lymphoma.
abstract: The latent membrane protein 1 (LMP1) oncogene is one of the major proteins synthesized by the Epstein-Barr virus (EBV). It is expressed in Reed-Sternberg cells of Hodgkin's disease (HD), tumor cells of nasopharyngeal carcinoma (NPC), and immunoblasts of angioimmunoblastic lymphadenopathy (AILD). A particular LMP1 deletion mutant was recently identified in NPC and clinically and histologically aggressive HD. We studied two patients with AILD that subsequently progressed into immunoblastic lymphoma (IBL) in order to investigate whether the LMP1 deletion mutant was implicated in progression of AILD into IBL. Immunohistology and in situ hybridization were performed on diagnostic biopsies. DNA extracted from fresh frozen material was used for rearrangement studies and polymerase chain reaction (PCR) based amplification and sequencing of portions of the LMP1 gene. Immunohistochemistry revealed B cell origin of both cases of IBL. In the first patient clonal rearrangement of the immunoglobulin heavy-chain gene was present in IBL but not in AILD. In this patient, scattered immunoblasts of AILD and numerous tumor cells of B-IBL were shown to contain EBV transcripts (EBER1) and to express LMP1. Sequence analysis of the LMP1 gene from AILD and IBL in the first, and from IBL in the second patient, revealed identical deletions and point mutations. This LMP1 deletion mutant is identical to those which have been reported in HD and NPC. Its association with evolution of AILD into B-IBL, aggressive HD and NPC, suggests that this particular mutant is more widespread than originally thought and is clinically relevant.
authors.affiliation: Department of Internal Medicine, CHUV University Hospital, Lausanne, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Knecht
authors.forename: F
authors.initials: F
authors.lastname: Martius
authors.forename: E
authors.initials: E
authors.lastname: Bachmann
authors.forename: T
authors.initials: T
authors.lastname: Hoffman
authors.forename: D R
authors.initials: DR
authors.lastname: Zimmermann
authors.forename: S
authors.initials: S
authors.lastname: Rothenberger
authors.forename: K
authors.initials: K
authors.lastname: Sandvej
authors.forename: W
authors.initials: W
authors.lastname: Wegmann
authors.forename: N
authors.initials: N
authors.lastname: Hurwitz
authors.forename: B F
authors.initials: BF
authors.lastname: Odermatt
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D017809:Fatal Outcome; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005814:Genes, Viral; D006566:Herpesviridae Infections / Q000821:virology; D004854:Herpesvirus 4, Human / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D007119:Immunoblastic Lymphadenopathy / Q000473:pathology* / Q000821:virology; D017403:In Situ Hybridization; D016393:Lymphoma, B-Cell / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009857:Oncogenes; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology* / Q000821:virology; D016539:Reed-Sternberg Cells / Q000821:virology; D017384:Sequence Deletion; D014412:Tumor Virus Infections / Q000821:virology; D014763:Viral Matrix Proteins / Q000235:genetics*; D015678:Viral Structural Proteins / Q000235:genetics*
chemical_list: D000956:Antigens, Viral; D004273:DNA, Neoplasm; D004279:DNA, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D015678:Viral Structural Proteins