Molecular analysis of latent membrane protein 1 in patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Japan.
Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is considered to be an oncoprotein because it is crucial for B-lymphocyte transformation. Since a 30 base pair (bp) deletion in the carboxy-terminal portion of the LMP1 gene was found in a CAO cell line derived from nasopharyngeal carcinoma containing EBV, an association between EB viral genetic alteration and tumorigenicity has been postulated. In this study we have analyzed LMP1 DNA isolated from 10 Japanese patients with EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). In all HLH patients, we found the 30 bp deletion and 4-8-tandem repeats of the sequence DNGPQDPDNTD in the LMP1 gene. Furthermore, detailed amino acid (aa) sequence analysis revealed that 7 aa substitutions identical to those found in CAO-LMP1 but not in B95.8 cell line-LMP1 were found in all the HLH cases. NF-kappaB assay revealed that HLH-LMP1 activated NF-kappaB significantly more than that of B95.8-LMP1 (p=0.032). We conclude that EBV from all of our HLH cases shared common genetic characteristics with EBV obtained from the CAO cell line, which is distinct from the wild-type EBV isolated from the B95.8 cell line. These data suggest that the mutational changes of the LMP1 gene may play an important role in the pathogenesis of these fatal EBV-related disorders.
Tabata YHibi
S
S
Department of Pediatrics, Kyoto Prefectural University of Medicine, Japan. tabata@ped.kpu-m.ac.jp
Teramura
T
T
Kuriyama
K
K
Yagi
T
T
Todo
S
S
Sawada
T
T
Imashuku
S
S
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002277:Carcinoma / Q000235:genetics / Q000821:virology; D002472:Cell Transformation, Viral; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000235:genetics* / Q000302:isolation & purification; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D005260:Female; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000302:isolation & purification; D015616:Histiocytosis, Non-Langerhans-Cell / Q000209:etiology / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D015994:Incidence; D007223:Infant; D007564:Japan / Q000453:epidemiology; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000821:virology; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014412:Tumor Virus Infections / Q000235:genetics / Q000821:virology; D014763:Viral Matrix Proteins / Q000096:biosynthesis / Q000235:genetics*
D004279:DNA, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D014763:Viral Matrix Proteins