title: LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis.
abstract: Epstein-Barr virus (EBV) infection transforms B cells in vitro and is associated with human B cell lymphomas. The major EBV oncoprotein, latent membrane protein 1 (LMP1), mimics constitutively active CD40 and is essential for outgrowth of EBV-transformed B cells in vitro; however, EBV-positive diffuse large B cell lymphomas and Burkitt lymphomas often express little or no LMP1. Thus, EBV may contribute to the development and maintenance of human lymphomas even in the absence of LMP1. Here, we found that i.p. injection of human cord blood mononuclear cells infected with a LMP1-deficient EBV into immunodeficient mice induces B cell lymphomas. In this model, lymphoma development required the presence of CD4+ T cells in cord blood and was inhibited by CD40-blocking Abs. In contrast, LMP1-deficient EBV established persistent latency but did not induce lymphomas when directly injected into mice engrafted with human fetal CD34+ cells and human thymus. WT EBV induced lymphomas in both mouse models and did not require coinjected T cells in the cord blood model. Together, these results demonstrate that LMP1 is not essential for EBV-induced lymphomas in vivo and suggest that T cells supply signals that substitute for LMP1 in EBV-positive B cell lymphomagenesis.
authors.forename: Shi-Dong
authors.initials: SD
authors.lastname: Ma
authors.forename: Xuequn
authors.initials: X
authors.lastname: Xu
authors.forename: Julie
authors.initials: J
authors.lastname: Plowshay
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Jensen
authors.forename: Fotis
authors.initials: F
authors.lastname: Asimakopoulos
authors.forename: Weihua
authors.initials: W
authors.lastname: Tang
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Gulley
authors.forename: Ethel
authors.initials: E
authors.lastname: Cesarman
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gumperz
authors.forename: Shannon C
authors.initials: SC
authors.lastname: Kenney
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D063646:Carcinogenesis; D049109:Cell Proliferation; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology; D015870:Gene Expression; D055786:Gene Knockout Techniques; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008223:Lymphoma / Q000276:immunology / Q000473:pathology / Q000821:virology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D017735:Virus Latency
chemical_list: D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins