Skip to main content
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1993 Nov;143(5):1270–1274.

Epstein-Barr virus infection and bcl-2 proto-oncogene expression. Separate events in the pathogenesis of Hodgkin's disease?

G Khan 1, R K Gupta 1, P J Coates 1, G Slavin 1
PMCID: PMC1887184  PMID: 8238244

Abstract

The present study was undertaken to investigate whether Epstein-Barr virus-(EBV) encoded latent membrane protein (LMP) induces the expression of BCL-2 in Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's disease (HD) and thereby provide a possible mechanism for the role of EBV in the pathogenesis of this disease. Fifty-three cases of HD were studied for the presence of EBV using EBV-encoded RNA in situ hybridization and LMP immunohistochemistry. Immunostaining for BCL-2 on paraffin material was performed using microwave treatment of tissue sections before the application of the primary monoclonal antibody. EBV was located in HRS cells in 16 cases (30%). All cases that were EBV-encoded RNA in situ hybridization positive, also expressed LMP. BCL-2 expression in HRS cells was detected in 16 cases (30%), but only two of these were also EBV-positive. In both of these cases, only occasional HRS cells expressed BCL-2, in contrast to LMP, which was detected in nearly all such cells. BCL-2 staining was predominantly cytoplasmic with some membrane pattern. These results demonstrate that BCL-2 expression can be detected in HRS cells in routinely processed HD tissue and that whereas EBV does not induce the expression of BCL-2 in HD, BCL-2 may have a role in the pathogenesis of EBV-negative cases of HD.

Full text

PDF
1270

Images in this article

Selected References

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

  1. Algara P., Martinez P., Sanchez L., Villuendas R., Orradre J. L., Oliva H., Piris M. A. Lymphocyte predominance Hodgkin's disease (nodular paragranuloma)--a bcl-2 negative germinal centre lymphoma. Histopathology. 1991 Jul;19(1):69–75. doi: 10.1111/j.1365-2559.1991.tb00896.x. [DOI] [PubMed] [Google Scholar]
  2. Armstrong A. A., Gallagher A., Krajewski A. S., Jones D. B., Wilkins B. S., Onions D. E., Jarrett R. F. The expression of the EBV latent membrane protein (LMP-1) is independent of CD23 and bcl-2 in Reed-Sternberg cells in Hodgkin's disease. Histopathology. 1992 Jul;21(1):72–73. doi: 10.1111/j.1365-2559.1992.tb00346.x. [DOI] [PubMed] [Google Scholar]
  3. Bissonnette R. P., Echeverri F., Mahboubi A., Green D. R. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature. 1992 Oct 8;359(6395):552–554. doi: 10.1038/359552a0. [DOI] [PubMed] [Google Scholar]
  4. Cabanillas F., Pathak S., Trujillo J., Grant G., Cork A., Hagemeister F. B., Velasquez W. S., McLaughlin P., Redman J., Katz R. Cytogenetic features of Hodgkin's disease suggest possible origin from a lymphocyte. Blood. 1988 Jun;71(6):1615–1617. [PubMed] [Google Scholar]
  5. Cattoretti G., Becker M. H., Key G., Duchrow M., Schlüter C., Galle J., Gerdes J. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992 Dec;168(4):357–363. doi: 10.1002/path.1711680404. [DOI] [PubMed] [Google Scholar]
  6. Coates P. J., Slavin G., D'Ardenne A. J. Persistence of Epstein-Barr virus in Reed-Sternberg cells throughout the course of Hodgkin's disease. J Pathol. 1991 Aug;164(4):291–297. doi: 10.1002/path.1711640404. [DOI] [PubMed] [Google Scholar]
  7. Fanidi A., Harrington E. A., Evan G. I. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature. 1992 Oct 8;359(6395):554–556. doi: 10.1038/359554a0. [DOI] [PubMed] [Google Scholar]
  8. Finke J., Fritzen R., Ternes P., Trivedi P., Bross K. J., Lange W., Mertelsmann R., Dölken G. Expression of bcl-2 in Burkitt's lymphoma cell lines: induction by latent Epstein-Barr virus genes. Blood. 1992 Jul 15;80(2):459–469. [PubMed] [Google Scholar]
  9. Gregory C. D., Dive C., Henderson S., Smith C. A., Williams G. T., Gordon J., Rickinson A. B. Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature. 1991 Feb 14;349(6310):612–614. doi: 10.1038/349612a0. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  12. Jacobson M. D., Burne J. F., King M. P., Miyashita T., Reed J. C., Raff M. C. Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature. 1993 Jan 28;361(6410):365–369. doi: 10.1038/361365a0. [DOI] [PubMed] [Google Scholar]
  13. Khan G., Coates P. J., Gupta R. K., Kangro H. O., Slavin G. Presence of Epstein-Barr virus in Hodgkin's disease is not exclusive to Reed-Sternberg cells. Am J Pathol. 1992 Apr;140(4):757–762. [PMC free article] [PubMed] [Google Scholar]
  14. Khan G., Coates P. J., Kangro H. O., Slavin G. Epstein Barr virus (EBV) encoded small RNAs: targets for detection by in situ hybridisation with oligonucleotide probes. J Clin Pathol. 1992 Jul;45(7):616–620. doi: 10.1136/jcp.45.7.616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lorenzen J., Hansmann M. L., Pezzella F., Hesse C., Kneba M., Gatter K. C., Fischer R. Expression of the bcl-2 oncogene product and chromosomal translocation t(14;18) in Hodgkin's disease. Hum Pathol. 1992 Nov;23(11):1205–1209. doi: 10.1016/0046-8177(92)90286-c. [DOI] [PubMed] [Google Scholar]
  16. Louie D. C., Kant J. A., Brooks J. J., Reed J. C. Absence of t(14;18) major and minor breakpoints and of Bcl-2 protein overproduction in Reed-Sternberg cells of Hodgkin's disease. Am J Pathol. 1991 Dec;139(6):1231–1237. [PMC free article] [PubMed] [Google Scholar]
  17. Lu Q. L., Elia G., Lucas S., Thomas J. A. Bcl-2 proto-oncogene expression in Epstein-Barr-virus-associated nasopharyngeal carcinoma. Int J Cancer. 1993 Jan 2;53(1):29–35. doi: 10.1002/ijc.2910530107. [DOI] [PubMed] [Google Scholar]
  18. Marchini A., Tomkinson B., Cohen J. I., Kieff E. BHRF1, the Epstein-Barr virus gene with homology to Bc12, is dispensable for B-lymphocyte transformation and virus replication. J Virol. 1991 Nov;65(11):5991–6000. doi: 10.1128/jvi.65.11.5991-6000.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. McDonnell T. J., Deane N., Platt F. M., Nunez G., Jaeger U., McKearn J. P., Korsmeyer S. J. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989 Apr 7;57(1):79–88. doi: 10.1016/0092-8674(89)90174-8. [DOI] [PubMed] [Google Scholar]
  20. Mueller N., Evans A., Harris N. L., Comstock G. W., Jellum E., Magnus K., Orentreich N., Polk B. F., Vogelman J. Hodgkin's disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med. 1989 Mar 16;320(11):689–695. doi: 10.1056/NEJM198903163201103. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Poppema S., Kaleta J., Hepperle B. Chromosomal abnormalities in patients with Hodgkin's disease: evidence for frequent involvement of the 14q chromosomal region but infrequent bcl-2 gene rearrangement in Reed-Sternberg cells. J Natl Cancer Inst. 1992 Dec 2;84(23):1789–1793. doi: 10.1093/jnci/84.23.1789. [DOI] [PubMed] [Google Scholar]
  23. Shi S. R., Key M. E., Kalra K. L. Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem. 1991 Jun;39(6):741–748. doi: 10.1177/39.6.1709656. [DOI] [PubMed] [Google Scholar]
  24. Stetler-Stevenson M., Crush-Stanton S., Cossman J. Involvement of the bcl-2 gene in Hodgkin's disease. J Natl Cancer Inst. 1990 May 16;82(10):855–858. doi: 10.1093/jnci/82.10.855. [DOI] [PubMed] [Google Scholar]
  25. Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
  26. Weiss L. M., Movahed L. A., Warnke R. A., Sklar J. Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin's disease. N Engl J Med. 1989 Feb 23;320(8):502–506. doi: 10.1056/NEJM198902233200806. [DOI] [PubMed] [Google Scholar]
  27. Weiss L. M., Strickler J. G., Warnke R. A., Purtilo D. T., Sklar J. Epstein-Barr viral DNA in tissues of Hodgkin's disease. Am J Pathol. 1987 Oct;129(1):86–91. [PMC free article] [PubMed] [Google Scholar]
  28. Zutter M., Hockenbery D., Silverman G. A., Korsmeyer S. J. Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms. Blood. 1991 Aug 15;78(4):1062–1068. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES