Skip to main content
NCBI home page
Clinical Molecular Pathology logoLink to Clinical Molecular Pathology
. 1995 Aug;48(4):M184–M187. doi: 10.1136/mp.48.4.m184

Deletions in the Epstein-Barr virus latent membrane protein-1 oncogene in Hodgkin's disease

A Santón 1,2, A I Manzanal 1,2, E Campo 1,2, C Bellas 1,2
PMCID: PMC407958  PMID: 16696002

Abstract

Aims—To analyse the latent membrane protein-1 (LMP-1) gene in a series of patients with Epstein-Barr virus (EBV) positive LMP expressing ordinary and HIV associated Hodgkin's disease to detect possible genetic alterations and particularly the existence of deletions near the 3′ end of the gene.

Methods—Expression of the EBV LMP-1 was assessed using immunohistochemistry in 186 cases of Hodgkin's disease and 31 cases of HIV associated Hodgkin's disease. Genomic DNA was extracted from frozen lymph node biopsy specimens from 25 cases of Hodgkin's disease and 11 of HIV associated Hodgkin's disease, all of whom expressed the LMP-1 protein within diagnostic Hodgkin and Reed-Sternberg (HRS) cells, and amplified by polymerase chain reaction (PCR) using primers specific for the different LMP-1 regions.

Results—LMP-1 expression was observed in 106 of 186 Hodgkin's disease cases and in all 31 HIV associated Hodgkin's disease cases. Molecular analysis of the LMP-1 gene showed a high degree of genetic heterogeneity in the carboxy-terminal domain compared with the prototype B95-8 EBV strain, specially in the patients with HIV associated Hodgkin's disease. Variation in the size of the repeated region was found in 17 of 25 Hodgkin's disease and nine of 11 HIV associated Hodgkin's disease cases. Deletions of 30 base pairs near the 3′ end of the gene were detected in all cases of HIV associated Hodgkin's disease and in six Hodgkin's disease. In one case of Hodgkin's disease a larger deletion was observed. In all patients with LMP-1 deletion mutants, 50-90% of the diagnostic HRS cells expressed the LMP-1 protein.

Conclusions—The presence of the 30 base pair deletion in all cases of HIV associated Hodgkin's disease supports previous studies that reported aggressive histological and clinical behaviour in tumours harbouring this deletion. This deletion may prolong the half-life of the protein which would explain the high levels of LMP-1 expressing HRS cells in those cases carrying LMP-1 deletions. That the 30 base pair deletion was present in all of the HIV associated Hodgkin's disease specimens suggests that impairment of immune function is a stringent requirement for the expansion of malignant cells infected by EBV strains containing the deleted LMP-1 gene.

Keywords: Epstein-Barr virus, latent membrane protein-1, Hodgkin's disease, HIV

Full text

PDF
M184

Images in this article

M186Image
on p.M186
M186Image
on p.M186

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Audouin J., Diebold J., Pallesen G. Frequent expression of Epstein-Barr virus latent membrane protein-1 in tumour cells of Hodgkin's disease in HIV-positive patients. J Pathol. 1992 Aug;167(4):381–384. doi: 10.1002/path.1711670406. [DOI] [PubMed] [Google Scholar]
  2. Baichwal V. R., Sugden B. Posttranslational processing of an Epstein-Barr virus-encoded membrane protein expressed in cells transformed by Epstein-Barr virus. J Virol. 1987 Mar;61(3):866–875. doi: 10.1128/jvi.61.3.866-875.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baichwal V. R., Sugden B. Transformation of Balb 3T3 cells by the BNLF-1 gene of Epstein-Barr virus. Oncogene. 1988 May;2(5):461–467. [PubMed] [Google Scholar]
  4. Boyle M. J., Vasak E., Tschuchnigg M., Turner J. J., Sculley T., Penny R., Cooper D. A., Tindall B., Sewell W. A. Subtypes of Epstein-Barr virus (EBV) in Hodgkin's disease: association between B-type EBV and immunocompromise. Blood. 1993 Jan 15;81(2):468–474. [PubMed] [Google Scholar]
  5. Carbone P. P., Kaplan H. S., Musshoff K., Smithers D. W., Tubiana M. Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res. 1971 Nov;31(11):1860–1861. [PubMed] [Google Scholar]
  6. Fennewald S., van Santen V., Kieff E. Nucleotide sequence of an mRNA transcribed in latent growth-transforming virus infection indicates that it may encode a membrane protein. J Virol. 1984 Aug;51(2):411–419. doi: 10.1128/jvi.51.2.411-419.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hammarskjöld M. L., Simurda M. C. Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-kappa B activity. J Virol. 1992 Nov;66(11):6496–6501. doi: 10.1128/jvi.66.11.6496-6501.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Henderson S., Rowe M., Gregory C., Croom-Carter D., Wang F., Longnecker R., Kieff E., Rickinson A. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991 Jun 28;65(7):1107–1115. doi: 10.1016/0092-8674(91)90007-l. [DOI] [PubMed] [Google Scholar]
  9. Herbst H., Dallenbach F., Hummel M., Niedobitek G., Pileri S., Müller-Lantzsch N., Stein H. Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4766–4770. doi: 10.1073/pnas.88.11.4766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hu L. F., Zabarovsky E. R., Chen F., Cao S. L., Ernberg I., Klein G., Winberg G. Isolation and sequencing of the Epstein-Barr virus BNLF-1 gene (LMP1) from a Chinese nasopharyngeal carcinoma. J Gen Virol. 1991 Oct;72(Pt 10):2399–2409. doi: 10.1099/0022-1317-72-10-2399. [DOI] [PubMed] [Google Scholar]
  11. Izumi K. M., Kaye K. M., Kieff E. D. Epstein-Barr virus recombinant molecular genetic analysis of the LMP1 amino-terminal cytoplasmic domain reveals a probable structural role, with no component essential for primary B-lymphocyte growth transformation. J Virol. 1994 Jul;68(7):4369–4376. doi: 10.1128/jvi.68.7.4369-4376.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kaye K. M., Izumi K. M., Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9150–9154. doi: 10.1073/pnas.90.19.9150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kaye K. M., Izumi K. M., Mosialos G., Kieff E. The Epstein-Barr virus LMP1 cytoplasmic carboxy terminus is essential for B-lymphocyte transformation; fibroblast cocultivation complements a critical function within the terminal 155 residues. J Virol. 1995 Feb;69(2):675–683. doi: 10.1128/jvi.69.2.675-683.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Khanna R., Burrows S. R., Kurilla M. G., Jacob C. A., Misko I. S., Sculley T. B., Kieff E., Moss D. J. Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development. J Exp Med. 1992 Jul 1;176(1):169–176. doi: 10.1084/jem.176.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Knecht H., Bachmann E., Brousset P., Sandvej K., Nadal D., Bachmann F., Odermatt B. F., Delsol G., Pallesen G. Deletions within the LMP1 oncogene of Epstein-Barr virus are clustered in Hodgkin's disease and identical to those observed in nasopharyngeal carcinoma. Blood. 1993 Nov 15;82(10):2937–2942. [PubMed] [Google Scholar]
  16. Knecht H., Bachmann E., Joske D. J., Sahli R., Eméry-Goodman A., Casanova J. L., Zilić M., Bachmann F., Odermatt B. F. Molecular analysis of the LMP (latent membrane protein) oncogene in Hodgkin's disease. Leukemia. 1993 Apr;7(4):580–585. [PubMed] [Google Scholar]
  17. Liebowitz D., Wang D., Kieff E. Orientation and patching of the latent infection membrane protein encoded by Epstein-Barr virus. J Virol. 1986 Apr;58(1):233–237. doi: 10.1128/jvi.58.1.233-237.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lukes R. J., Butler J. J. The pathology and nomenclature of Hodgkin's disease. Cancer Res. 1966 Jun;26(6):1063–1083. [PubMed] [Google Scholar]
  19. Mann K. P., Thorley-Lawson D. Posttranslational processing of the Epstein-Barr virus-encoded p63/LMP protein. J Virol. 1987 Jul;61(7):2100–2108. doi: 10.1128/jvi.61.7.2100-2108.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Martin J., Sugden B. Transformation by the oncogenic latent membrane protein correlates with its rapid turnover, membrane localization, and cytoskeletal association. J Virol. 1991 Jun;65(6):3246–3258. doi: 10.1128/jvi.65.6.3246-3258.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miller W. E., Edwards R. H., Walling D. M., Raab-Traub N. Sequence variation in the Epstein-Barr virus latent membrane protein 1. J Gen Virol. 1994 Oct;75(Pt 10):2729–2740. doi: 10.1099/0022-1317-75-10-2729. [DOI] [PubMed] [Google Scholar]
  22. Moorthy R. K., Thorley-Lawson D. A. All three domains of the Epstein-Barr virus-encoded latent membrane protein LMP-1 are required for transformation of rat-1 fibroblasts. J Virol. 1993 Mar;67(3):1638–1646. doi: 10.1128/jvi.67.3.1638-1646.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Moorthy R. K., Thorley-Lawson D. A. Biochemical, genetic, and functional analyses of the phosphorylation sites on the Epstein-Barr virus-encoded oncogenic latent membrane protein LMP-1. J Virol. 1993 May;67(5):2637–2645. doi: 10.1128/jvi.67.5.2637-2645.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Moorthy R., Thorley-Lawson D. A. Processing of the Epstein-Barr virus-encoded latent membrane protein p63/LMP. J Virol. 1990 Feb;64(2):829–837. doi: 10.1128/jvi.64.2.829-837.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mosialos G., Birkenbach M., Yalamanchili R., VanArsdale T., Ware C., Kieff E. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell. 1995 Feb 10;80(3):389–399. doi: 10.1016/0092-8674(95)90489-1. [DOI] [PubMed] [Google Scholar]
  26. Pallesen G., Hamilton-Dutoit S. J., Rowe M., Young L. S. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet. 1991 Feb 9;337(8737):320–322. doi: 10.1016/0140-6736(91)90943-j. [DOI] [PubMed] [Google Scholar]
  27. Rubio R. Hodgkin's disease associated with human immunodeficiency virus infection. A clinical study of 46 cases. Cooperative Study Group of Malignancies Associated with HIV Infection of Madrid. Cancer. 1994 May 1;73(9):2400–2407. doi: 10.1002/1097-0142(19940501)73:9<2400::aid-cncr2820730925>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  28. Samoszuk M., Ravel J. Frequent detection of Epstein-Barr viral deoxyribonucleic acid and absence of cytomegalovirus deoxyribonucleic acid in Hodgkin's disease and acquired immunodeficiency syndrome-related Hodgkin's disease. Lab Invest. 1991 Dec;65(6):631–636. [PubMed] [Google Scholar]
  29. Sample J., Kieff E. F., Kieff E. D. Epstein-Barr virus types 1 and 2 have nearly identical LMP-1 transforming genes. J Gen Virol. 1994 Oct;75(Pt 10):2741–2746. doi: 10.1099/0022-1317-75-10-2741. [DOI] [PubMed] [Google Scholar]
  30. Sample J., Young L., Martin B., Chatman T., Kieff E., Rickinson A., Kieff E. Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J Virol. 1990 Sep;64(9):4084–4092. doi: 10.1128/jvi.64.9.4084-4092.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sandvej K., Peh S. C., Andresen B. S., Pallesen G. Identification of potential hot spots in the carboxy-terminal part of the Epstein-Barr virus (EBV) BNLF-1 gene in both malignant and benign EBV-associated diseases: high frequency of a 30-bp deletion in Malaysian and Danish peripheral T-cell lymphomas. Blood. 1994 Dec 15;84(12):4053–4060. [PubMed] [Google Scholar]
  32. Serrano M., Bellas C., Campo E., Ribera J., Martín C., Rubio R., Ruiz C., Ocaña I., Buzón L., Yebra M. Hodgkin's disease in patients with antibodies to human immunodeficiency virus. A study of 22 patients. Cancer. 1990 May 15;65(10):2248–2254. doi: 10.1002/1097-0142(19900515)65:10<2248::aid-cncr2820651015>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  33. Wang D., Liebowitz D., Wang F., Gregory C., Rickinson A., Larson R., Springer T., Kieff E. Epstein-Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino terminus abolishes activity. J Virol. 1988 Nov;62(11):4173–4184. doi: 10.1128/jvi.62.11.4173-4184.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Clinical Molecular Pathology are provided here courtesy of BMJ Publishing Group

RESOURCES