Abstract
Epstein-Barr virus (EBV) genome has been detected in several human lymphoproliferative diseases, but the oncogenic function of EBV is not fully understood. We previously established EBV-positive (SP-50B) and EBV-negative (SP-53) cell lines with the t(11;14)(q13;q32) chromosome abnormality from a single patient with mantle cell lymphoma. Monoclonal EBV DNA in a circular episomal form was demonstrated in the SP-50B cells by Southern blot hybridization with the EBV-terminal fragment probe. SP-50B cells were positive for not only EBV-encoded nuclear antigen-1 (EBNA1) but also latent membrane protein-1 and EBNA2. None of the EBV-encoded proteins was expressed in SP-53 cells. The isogenic EBV-infected and EBV-free cell lines of neoplastic clones made it possible to examine a tumorigenic role of EBV. Only EBV-positive SP-50B cells possessed malignant phenotypes, such as growth ability in low serum, colony formation in soft agarose, and tumorigenicity in nude mice. On the other hand, a lymphoblastoid B-cell line established by infecting the patient's normal B lymphocytes in vitro with exogenous EBV had no tumorigenicity. These results suggested that EBV infection, if it occurred in neoplastic lymphoma cells, could play a role in acquisition of malignant phenotypes.
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- Abbot S. D., Rowe M., Cadwallader K., Ricksten A., Gordon J., Wang F., Rymo L., Rickinson A. B. Epstein-Barr virus nuclear antigen 2 induces expression of the virus-encoded latent membrane protein. J Virol. 1990 May;64(5):2126–2134. doi: 10.1128/jvi.64.5.2126-2134.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arvanitakis L., Yaseen N., Sharma S. Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells. J Immunol. 1995 Aug 1;155(3):1047–1056. [PubMed] [Google Scholar]
- Banks P. M., Chan J., Cleary M. L., Delsol G., De Wolf-Peeters C., Gatter K., Grogan T. M., Harris N. L., Isaacson P. G., Jaffe E. S. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol. 1992 Jul;16(7):637–640. doi: 10.1097/00000478-199207000-00001. [DOI] [PubMed] [Google Scholar]
- Criel A., Billiet J., Vandenberghe E., van den Berghe H., Louwagie A., Hidajat M., Vanhoof A. Leukaemic intermediate lymphocytic lymphomas: analysis of twelve cases diagnosed by morphology. Leuk Lymphoma. 1992 Nov;8(4-5):381–387. doi: 10.3109/10428199209051018. [DOI] [PubMed] [Google Scholar]
- Cutrona G., Ulivi M., Fais F., Roncella S., Ferrarini M. Transfection of the c-myc oncogene into normal Epstein-Barr virus-harboring B cells results in new phenotypic and functional features resembling those of Burkitt lymphoma cells and normal centroblasts. J Exp Med. 1995 Feb 1;181(2):699–711. doi: 10.1084/jem.181.2.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Daibata M., Kubonishi I., Eguchi T., Yano S., Ohtsuki Y., Miyoshi I. The establishment of Epstein-Barr virus nuclear antigen-positive (SP-50B) and Epstein-Barr virus nuclear antigen-negative (SP-53) cell lines with t(11;14)(q13;q32) chromosome abnormality from an intermediate lymphocytic lymphoma. Cancer. 1989 Sep 15;64(6):1248–1253. doi: 10.1002/1097-0142(19890915)64:6<1248::aid-cncr2820640614>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
- Diabata M., Enzinger E. M., Monroe J. E., Kilkuskie R. E., Field A. K., Mulder C. Antisense oligodeoxynucleotides against the BZLF1 transcript inhibit induction of productive Epstein-Barr virus replication. Antiviral Res. 1996 Mar;29(2-3):243–260. doi: 10.1016/0166-3542(95)00902-7. [DOI] [PubMed] [Google Scholar]
- Gratama J. W., Zutter M. M., Minarovits J., Oosterveer M. A., Thomas E. D., Klein G., Ernberg I. Expression of Epstein-Barr virus-encoded growth-transformation-associated proteins in lymphoproliferations of bone-marrow transplant recipients. Int J Cancer. 1991 Jan 21;47(2):188–192. doi: 10.1002/ijc.2910470205. [DOI] [PubMed] [Google Scholar]
- Hanto D. W., Frizzera G., Gajl-Peczalska K. J., Sakamoto K., Purtilo D. T., Balfour H. H., Jr, Simmons R. L., Najarian J. S. Epstein-Barr virus-induced B-cell lymphoma after renal transplantation: acyclovir therapy and transition from polyclonal to monoclonal B-cell proliferation. N Engl J Med. 1982 Apr 15;306(15):913–918. doi: 10.1056/NEJM198204153061506. [DOI] [PubMed] [Google Scholar]
- 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]
- Hinds P. W., Dowdy S. F., Eaton E. N., Arnold A., Weinberg R. A. Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):709–713. doi: 10.1073/pnas.91.2.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hummel M., Tamaru J., Kalvelage B., Stein H. Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle. Blood. 1994 Jul 15;84(2):403–407. [PubMed] [Google Scholar]
- Knutson J. C. The level of c-fgr RNA is increased by EBNA-2, an Epstein-Barr virus gene required for B-cell immortalization. J Virol. 1990 Jun;64(6):2530–2536. doi: 10.1128/jvi.64.6.2530-2536.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lacy J., Summers W. P., Summers W. C. Post-transcriptional mechanisms of deregulation of MYC following conversion of a human B cell line by Epstein-Barr virus. EMBO J. 1989 Jul;8(7):1973–1980. doi: 10.1002/j.1460-2075.1989.tb03603.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lacy J., Summers W. P., Watson M., Glazer P. M., Summers W. C. Amplification and deregulation of MYC following Epstein-Barr virus infection of a human B-cell line. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5838–5842. doi: 10.1073/pnas.84.16.5838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lombardi L., Newcomb E. W., Dalla-Favera R. Pathogenesis of Burkitt lymphoma: expression of an activated c-myc oncogene causes the tumorigenic conversion of EBV-infected human B lymphoblasts. Cell. 1987 Apr 24;49(2):161–170. doi: 10.1016/0092-8674(87)90556-3. [DOI] [PubMed] [Google Scholar]
- MacMahon E. M., Glass J. D., Hayward S. D., Mann R. B., Becker P. S., Charache P., McArthur J. C., Ambinder R. F. Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet. 1991 Oct 19;338(8773):969–973. doi: 10.1016/0140-6736(91)91837-k. [DOI] [PubMed] [Google Scholar]
- 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]
- Motokura T., Bloom T., Kim H. G., Jüppner H., Ruderman J. V., Kronenberg H. M., Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. doi: 10.1038/350512a0. [DOI] [PubMed] [Google Scholar]
- Palmero I., Holder A., Sinclair A. J., Dickson C., Peters G. Cyclins D1 and D2 are differentially expressed in human B-lymphoid cell lines. Oncogene. 1993 Apr;8(4):1049–1054. [PubMed] [Google Scholar]
- Raab-Traub N., Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell. 1986 Dec 26;47(6):883–889. doi: 10.1016/0092-8674(86)90803-2. [DOI] [PubMed] [Google Scholar]
- Raffeld M., Jaffe E. S. bcl-1, t(11;14), and mantle cell-derived lymphomas. Blood. 1991 Jul 15;78(2):259–263. [PubMed] [Google Scholar]
- Rimokh R., Berger F., Delsol G., Charrin C., Berthéas M. F., Ffrench M., Garoscio M., Felman P., Coiffier B., Bryon P. A. Rearrangement and overexpression of the BCL-1/PRAD-1 gene in intermediate lymphocytic lymphomas and in t(11q13)-bearing leukemias. Blood. 1993 Jun 1;81(11):3063–3067. [PubMed] [Google Scholar]
- Rowe M., Evans H. S., Young L. S., Hennessy K., Kieff E., Rickinson A. B. Monoclonal antibodies to the latent membrane protein of Epstein-Barr virus reveal heterogeneity of the protein and inducible expression in virus-transformed cells. J Gen Virol. 1987 Jun;68(Pt 6):1575–1586. doi: 10.1099/0022-1317-68-6-1575. [DOI] [PubMed] [Google Scholar]
- Seto M., Yamamoto K., Iida S., Akao Y., Utsumi K. R., Kubonishi I., Miyoshi I., Ohtsuki T., Yawata Y., Namba M. Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation. Oncogene. 1992 Jul;7(7):1401–1406. [PubMed] [Google Scholar]
- Shimakage M., Kurata A., Inoue H., Okamoto Y., Yutsudo M., Hakura A. Tumorigenicity of EBNA2-transfected cells. FEBS Lett. 1995 Sep 11;371(3):245–248. doi: 10.1016/0014-5793(95)00889-h. [DOI] [PubMed] [Google Scholar]
- Shimizu N., Tanabe-Tochikura A., Kuroiwa Y., Takada K. Isolation of Epstein-Barr virus (EBV)-negative cell clones from the EBV-positive Burkitt's lymphoma (BL) line Akata: malignant phenotypes of BL cells are dependent on EBV. J Virol. 1994 Sep;68(9):6069–6073. doi: 10.1128/jvi.68.9.6069-6073.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sinclair A. J., Palmero I., Holder A., Peters G., Farrell P. J. Expression of cyclin D2 in Epstein-Barr virus-positive Burkitt's lymphoma cell lines is related to methylation status of the gene. J Virol. 1995 Feb;69(2):1292–1295. doi: 10.1128/jvi.69.2.1292-1295.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sinclair A. J., Palmero I., Peters G., Farrell P. J. EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. EMBO J. 1994 Jul 15;13(14):3321–3328. doi: 10.1002/j.1460-2075.1994.tb06634.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vandenberghe E. Mantle cell lymphoma. Blood Rev. 1994 Jun;8(2):79–87. doi: 10.1016/s0268-960x(05)80011-6. [DOI] [PubMed] [Google Scholar]
- Wang D., Liebowitz D., Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985 Dec;43(3 Pt 2):831–840. doi: 10.1016/0092-8674(85)90256-9. [DOI] [PubMed] [Google Scholar]
- Wang F., Tsang S. F., Kurilla M. G., Cohen J. I., Kieff E. Epstein-Barr virus nuclear antigen 2 transactivates latent membrane protein LMP1. J Virol. 1990 Jul;64(7):3407–3416. doi: 10.1128/jvi.64.7.3407-3416.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- Wennborg A., Aman P., Saranath D., Pear W., Sümegi J., Klein G. Conversion of the lymphoma line "BJAB" by Epstein-Barr virus into phenotypically altered sublines is accompanied by increased c-myc mRNA levels. Int J Cancer. 1987 Aug 15;40(2):202–206. doi: 10.1002/ijc.2910400213. [DOI] [PubMed] [Google Scholar]
- Williams M. E., Meeker T. C., Swerdlow S. H. Rearrangement of the chromosome 11 bcl-1 locus in centrocytic lymphoma: analysis with multiple breakpoint probes. Blood. 1991 Jul 15;78(2):493–498. [PubMed] [Google Scholar]
- Young L., Alfieri C., Hennessy K., Evans H., O'Hara C., Anderson K. C., Ritz J., Shapiro R. S., Rickinson A., Kieff E. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med. 1989 Oct 19;321(16):1080–1085. doi: 10.1056/NEJM198910193211604. [DOI] [PubMed] [Google Scholar]
- Zutter M. M., Martin P. J., Sale G. E., Shulman H. M., Fisher L., Thomas E. D., Durnam D. M. Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood. 1988 Aug;72(2):520–529. [PubMed] [Google Scholar]