Viral latent membrane protein 1 (LMP-1)-induced CD99 down-regulation in B cells leads to the generation of cells with Hodgkin's and Reed-Sternberg phenotype.
Recently we reported that the down-regulation of CD99 (Mic2) is a primary requirement for the generation of Hodgkin's and Reed-Sternberg (H-RS) cells seen in Hodgkin's disease. In this study, we provide evidence that the down-regulation of CD99 is induced by high expression of Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1), which is highly expressed in H-RS cells of EBV-associated Hodgkin's disease. To investigate the effect of LMP-1 on the expression of CD99 in vitro, we established a stable cell line by transfecting an SV40-early promoter driven-LMP-1 expression construct into a neoplastic lymphoblastoid B cell line, IM9, in which the level of endogenous LMP-1 expression is almost negligible. In this cell line, the overexpression of LMP-1 led to the down-regulation of CD99 and the acquisition of morphological and functional characteristics of H-RS cells indistinguishable from those in lymph nodes of Hodgkin's disease patients and in CD99-deficient B cells. In addition, induced LMP-1 expression in an EBV-negative B cell clone, BJAB, directly caused the down-regulation of surface CD99 expression. Northern and Western analysis data, showing that overexpression of LMP-1 negatively influenced the expression of CD99, were supported by experiments in which a CD99 promoter-driven luciferase promoter reporter construct transfected into 293T cells was down-regulated when LMP-1 was coexpressed. Therefore, our data strongly suggest that the EBV LMP-1 protein plays a pivotal role in the down-regulation of CD99 via transcriptional regulation, which leads to the generation of the H-RS cells. (Blood. 2000;95:294-300)
Kim
S H
SH
Department of Pathology, Institute of Allergy and Clinical Immunology, Seoul National University College of Medicine, Seoul, Korea.
Shin
Y K
YK
Lee
I S
IS
Bae
Y M
YM
Sohn
H W
HW
Suh
Y H
YH
Ree
H J
HJ
Rowe
M
M
Park
S H
SH
D000071443:12E7 Antigen; D000782:Aneuploidy; D015703:Antigens, CD / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007668:Kidney; D008156:Luciferases / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000276:immunology; D016539:Reed-Sternberg Cells / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
D000071443:12E7 Antigen; D015703:Antigens, CD; C061828:CD99 protein, human; D015815:Cell Adhesion Molecules; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins; D008156:Luciferases