DOI QR코드

DOI QR Code

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

  • Lee, Im-Soon (Department of Biological Sciences and Center for Biotechnology Research in UBITA (CBRU), Konkuk University)
  • Received : 2001.08.23
  • Accepted : 2011.08.26
  • Published : 2011.10.30

Abstract

Over the past few decades, our understanding of the epidemiology and immunopathogenesis of Hodgkin lymphoma (HL) has made enormous advances. Consequently, the treatment of HL has changed significantly, rendering this disease of the most curable human cancers. To date, about 80% of patients achieve long-term disease-free survival. However, therapeutic challenges still remain, particularly regarding the salvage strategies for relapsed and refractory disease, which need further identification of better prognostic markers and novel therapeutic schemes. Although the precise molecular mechanism by which Epstein-Barr virus (EBV) contributes to the generation of malignant cells present in HL still remains unknown, current increasing data on the role of EBV in the pathobiology of HL have encouraged people to start developing novel and specific therapeutic strategies for EBV-associated HL. This review will provide an overview of therapeutic approaches for acute EBV infection and the classical form of HL (cHL), especially focusing on EBV-associated HL cases.

Keywords

References

  1. Adams, J. (2003) Potential for proteasome inhibition in the treatment of cancer. Drug Discov. Today 8, 307-315. https://doi.org/10.1016/S1359-6446(03)02647-3
  2. Aldinucci, D., Gloghini, A., Pinto, A., De Filippi, R. and Carbone, A. (2010) The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape. J. Pathol. 221, 248-263. https://doi.org/10.1002/path.2711
  3. Ambinder, R. F., Browning, P. J., Lorenzana, I., Leventhal, B. G., Cosenza, H., Mann, R. B., MacMahon, E. M., Medina, R., Cardona, V., Grufferman, S. and et al. (1993) Epstein-Barr virus and childhood Hodgkin's disease in Honduras and the United States. Blood 81, 462-467. https://doi.org/10.1002/path.2711
  4. Anderson, L. J. and Longnecker, R. (2008) An auto-regulatory loop for EBV LMP2A involves activation of Notch. Virology 371, 257-266. https://doi.org/10.1016/j.virol.2007.10.009
  5. Ansell, S. M., Horwitz, S. M., Engert, A., Khan, K. D., Lin, T., Strair, R., Keler, T., Graziano, R., Blanset, D., Yellin, M., Fischkoff, S., Assad, A. and Borchmann, P. (2007) Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin's lymphoma and anaplastic large-cell lymphoma. J. Clin. Oncol. 25, 2764-2769. https://doi.org/10.1200/JCO.2006.07.8972
  6. Asso-Bonnet, M., Feuillard, J., Ferreira, V., Bissieres, P., Tarantino, N., Korner, M. and Raphael, M. (1998) Relationship between IkappaBalpha constitutive expression, TNFalpha synthesis, and apoptosis in EBV-infected lymphoblastoid cells. Oncogene 17, 1607-1615. https://doi.org/10.1038/sj.onc.1202365
  7. Bartlett, J. B., Dredge, K. and Dalgleish, A. G. (2004) The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 4, 314-322. https://doi.org/10.1038/nrc1323
  8. Baud, V. and Karin, M. (2009) Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat. Rev. Drug Discov. 8, 33-40. https://doi.org/10.1038/nrd2781
  9. Bechtel, D., Kurth, J., Unkel, C. and Kuppers, R. (2005) Transformation of BCR-defi cient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 106, 4345-4350. https://doi.org/10.1182/blood-2005-06-2342
  10. Blum, K. A., Jung, S. H., Johnson, J. L., Lin, T. S., Hsi, E. D., Lucas, D. M., Byrd, J. C., Cheson, B. D. and Bartlett, N. L. (2010) Serious pulmonary toxicity in patients with Hodgkin's lymphoma with SGN-30, gemcitabine, vinorelbine, and liposomal doxorubicin is associated with an FcgammaRIIIa-158 V/F polymorphism. Ann. Oncol. 21, 2246-2254. https://doi.org/10.1093/annonc/mdq211
  11. Bolden, J. E., Peart, M. J. and Johnstone, R. W. (2006) Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769-784. https://doi.org/10.1038/nrd2133
  12. Boleti, E. and Mead, G. M. (2007) ABVD for Hodgkin's lymphoma: full-dose chemotherapy without dose reductions or growth factors. Ann. Oncol. 18, 376-380.
  13. Boll, B., Borchmann, P., Topp, M.S., Hanel, M., Reiners, K. S., Engert, A. and Naumann, R. (2010) Lenalidomide in patients with refractory or multiple relapsed Hodgkin lymphoma. Br. J. Haematol. 148, 480-482. https://doi.org/10.1111/j.1365-2141.2009.07963.x
  14. Boumber, Y., Younes, A. and Garcia-Manero, G. (2011) Mocetinostat (MGCD0103): a review of an isotype-specifi c histone deacetylase inhibitor. Expert Opin. Investig. Drugs 20, 823-829. https://doi.org/10.1517/13543784.2011.577737
  15. Boyd, M. R., Cole, M., Harnden, M. R., Luk, K., Rush, M. A., Sutton, D. and Hodge, R. A. (1986) Improvement of the bioavailability of the anti-herpes virus agent BVDU by use of 5'-O-alkoxycarbonyl derivatives with increased metabolic stability. J. Antimicrob. Chemother. 18, 207-213.
  16. Brink, A. A., Oudejans, J. J., Jiwa, M., Walboomers, J. M., Meijer, C. J. and van den Brule, A. J. (1997) Multiprimed cDNA synthesis followed by PCR is the most suitable method for Epstein-Barr virus transcript analysis in small lymphoma biopsies. Mol. Cell Probes 11, 39-47. https://doi.org/10.1006/mcpr.1996.0074
  17. Brogdon, J. L., Xu, Y., Szabo, S. J., An, S., Buxton, F., Cohen, D. and Huang, Q. (2007) Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 109, 1123-1130.
  18. Carbone, A., Gloghini, A., Serraino, D. and Spina, M. (2009) HIV-associated Hodgkin lymphoma. Curr. Opin. HIV AIDS 4, 3-10. https://doi.org/10.1097/COH.0b013e32831a722b
  19. Carbone, A., Spina, M., Gloghini, A. and Tirelli, U. (2011) Classical Hodgkin's lymphoma arising in different host's conditions: pathobiology parameters, therapeutic options, and outcome. Am. J. Hematol. 86, 170-179. https://doi.org/10.1002/ajh.21910
  20. Chan, W. C. (1999) Cellular origin of nodular lymphocyte-predominant Hodgkin's lymphoma: immunophenotypic and molecular studies. Semin. Hematol. 36, 242-252.
  21. Chang, K. L., Albujar, P. F., Chen, Y. Y., Johnson, R. M. and Weiss, L. M. (1993) High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of Hodgkin's disease occurring in Peru. Blood 81, 496-501.
  22. Chapman, A. L., Rickinson, A. B., Thomas, W. A., Jarrett, R. F., Crocker, J. and Lee, S. P. (2001) Epstein-Barr virus-specifi c cytotoxic T lymphocyte responses in the blood and tumor site of Hodgkin's disease patients: implications for a T-cell-based therapy. Cancer Res. 61, 6219-6226.
  23. Chen, H., Hutt-Fletcher, L., Cao, L. and Hayward, S. D. (2003) A positive autoregulatory loop of LMP1 expression and STAT activation in epithelial cells latently infected with Epstein-Barr virus. J. Virol. 77, 4139-4148. https://doi.org/10.1128/JVI.77.7.4139-4148.2003
  24. Chia, W. K., Wang, W. W., Teo, M., Tai, W. M., Lim, W. T., Tan, E. H., Leong, S. S., Sun, L., Chen, J. J., Gottschalk, S. and Toh, H. C. (2011) A phase II study evaluating the safety and effi cacy of an adenovirus-dLMP1-LMP2 transduced dendritic cell in patients with advanced metastatic nasopharyngeal carcinoma. Ann. Oncol. Aug 4. [Epub ahead of print]
  25. Chiang, A. K., Tao, Q., Srivastava, G. and Ho, F. C. (1996) Nasal NKand T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin's disease. Int. J. Cancer 68, 285-290. https://doi.org/10.1002/(SICI)1097-0215(19961104)68:3<285::AID-IJC3>3.0.CO;2-Y
  26. Clarke, C. A., Glaser, S. L., Dorfman, R. F., Mann, R., DiGiuseppe, J. A., Prehn, A. W. and Ambinder, R. F. (2001) Epstein-Barr virus and survival after Hodgkin disease in a population-based series of women. Cancer 91, 1579-1587. https://doi.org/10.1002/1097-0142(20010415)91:8<1579::AID-CNCR1169>3.0.CO;2-L
  27. Cleary, S. F., Link, M. P. and Donaldson, S. S. (1994) Hodgkin's disease in the very young. Int. J. Radiat. Oncol. Biol. Phys. 28, 77-83. https://doi.org/10.1016/0360-3016(94)90143-0
  28. Clodi, K. and Younes, A. (1997) Reed-Sternberg cells and the TNF family of receptors/ligands. Leuk. Lymphoma 27, 195-205.
  29. Coiffi er, B., Haioun, C., Ketterer, N., Engert, A., Tilly, H., Ma, D., Johnson, P., Lister, A., Feuring-Buske, M., Radford, J. A., Capdeville, R., Diehl, V. and Reyes, F. (1998) Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92, 1927-1932.
  30. Connors, J. M., Noordijk, E. M. and Horning, S. J. (2001) Hodgkin's lymphoma: basing the treatment on the evidence. Hematology Am. Soc. Hematol. Educ. Program 178-193.
  31. Daigle, D., Gradoville, L., Tuck, D., Schulz, V., Wang'ondu, R., Ye, J., Gorres, K. and Miller, G. (2011) Valproic acid antagonizes the capacity of other histone deacetylase inhibitors to activate the Epstein-barr virus lytic cycle. J. Virol. 85, 5628-5643. https://doi.org/10.1128/JVI.02659-10
  32. Dantuma, N. P., Heessen, S., Lindsten, K., Jellne, M. and Masucci, M. G. (2000) Inhibition of proteasomal degradation by the gly-Ala repeat of Epstein-Barr virus is infl uenced by the length of the repeat and the strength of the degradation signal. Proc. Natl. Acad. Sci. USA 97, 8381-8385. https://doi.org/10.1073/pnas.140217397
  33. Datta, A. K. and Hood, R. E. (1981) Mechanism of inhibition of Epstein- Barr virus replication by phosphonoformic acid. Virology 114, 52-59. https://doi.org/10.1016/0042-6822(81)90251-8
  34. Deacon, E. M., Pallesen, G., Niedobitek, G., Crocker, J., Brooks, L., Rickinson, A. B. and Young, L. S. (1993) Epstein-Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J. Exp. Med. 177, 339-349. https://doi.org/10.1084/jem.177.2.339
  35. Delbende, C., Verwaerde, C., Mougel, A. and Tranchand Bunel, D. (2009) Induction of therapeutic antibodies by vaccination against external loops of tumor-associated viral latent membrane protein. J. Virol. 83, 11734-11745. https://doi.org/10.1128/JVI.00578-09
  36. Dickinson, M., Ritchie, D., DeAngelo, D. J., Spencer, A., Ottmann, O. G., Fischer, T., Bhalla, K. N., Liu, A., Parker, K., Scott, J. W., Bishton, M. and Prince, H. M. (2009) Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma. Br. J. Haematol. 147, 97-101. https://doi.org/10.1111/j.1365-2141.2009.07837.x
  37. Diehl, V., Franklin, J., Hasenclever, D., Tesch, H., Pfreundschuh, M., Lathan, B., Paulus, U., Sieber, M., Rueffer, J. U., Sextro, M., Engert, A., Wolf, J., Hermann, R., Holmer, L., Stappert-Jahn, U., Winnerlein-Trump, E., Wulf, G., Krause, S., Glunz, A., von Kalle, K., Bischoff, H., Haedicke, C., Duehmke, E., Georgii, A. and Loeffl er, M. (1998a) BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group. J. Clin. Oncol. 16, 3810-3821.
  38. Diehl, V., Franklin, J., Hasenclever, D., Tesch, H., Pfreundschuh, M., Lathan, B., Paulus, U., Sieber, M., Ruffer, J. U., Sextro, M., Engert, A., Wolf, J., Hermann, R., Holmer, L., Stappert-Jahn, U., Winnerlein-Trump, E., Wulf, G., Krause, S., Glunz, A., von Kalle, K., Bischoff, H., Haedicke, C., Duhmke, E., Georgii, A. and Loeffl er, M. (1998b) BEACOPP: a new regimen for advanced Hodgkin's disease. German Hodgkin's Lymphoma Study Group. Ann. Oncol. 9, S67-71. https://doi.org/10.1023/A:1008451300320
  39. Diehl, V., Sieber, M., Ruffer, U., Lathan, B., Hasenclever, D., Pfreundschuh, M., Loeffl er, M., Lieberz, D., Koch, P., Adler, M. and Tesch, H. (1997) BEACOPP: an intensifi ed chemotherapy regimen in advanced Hodgkin's disease. The German Hodgkin's Lymphoma Study Group. Ann. Oncol. 8, 143-148. https://doi.org/10.1023/A:1008294312741
  40. Diehl, V., Stein, H., Hummel, M., Zollinger, R. and Connors, J. M. (2003) Hodgkin's lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease. Hematology Am. Soc. Hematol. Educ. Program 225-247.
  41. Duraiswamy, J., Sherritt, M., Thomson, S., Tellam, J., Cooper, L., Connolly, G., Bharadwaj, M. and Khanna, R. (2003) Therapeutic LMP1 polyepitope vaccine for EBV-associated Hodgkin disease and nasopharyngeal carcinoma. Blood 101, 3150-3156. https://doi.org/10.1182/blood-2002-10-3092
  42. Eberle, F. C., Mani, H. and Jaffe, E. S. (2009) Histopathology of Hodgkin's lymphoma. Cancer J. 15, 129-137. https://doi.org/10.1097/PPO.0b013e31819e31cf
  43. Enblad, G., Sandvej, K., Sundstrom, C., Pallesen, G. and Glimelius, B. (1999) Epstein-Barr virus distribution in Hodgkin's disease in an unselected Swedish population. Acta. Oncol. 38, 425-429. https://doi.org/10.1080/028418699431942
  44. Engert, A., Diehl, V., Franklin, J., Lohri, A., Dorken, B., Ludwig, W. D., Koch, P., Hanel, M., Pfreundschuh, M., Wilhelm, M., Trumper, L., Aulitzky, W. E., Bentz, M., Rummel, M., Sezer, O., Muller-Hermelink, H. K., Hasenclever, D. and Loffl er, M. (2009) Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J. Clin. Oncol. 27, 4548-4554. https://doi.org/10.1200/JCO.2008.19.8820
  45. Fiumara, P., Snell, V., Li, Y., Mukhopadhyay, A., Younes, M., Gillenwater, A. M., Cabanillas, F., Aggarwal, B. B. and Younes, A. (2001) Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. Blood 98, 2784-2790. https://doi.org/10.1182/blood.V98.9.2784
  46. Flanagan, J., Middeldorp, J. and Sculley, T. (2003) Localization of the Epstein-Barr virus protein LMP 1 to exosomes. J. Gen. Virol. 84, 1871-1879. https://doi.org/10.1099/vir.0.18944-0
  47. Flavell, K. J., Biddulph, J. P., Constandinou, C. M., Lowe, D., Scott, K., Crocker, J., Young, L. S. and Murray, P. G. (2000) Variation in the frequency of Epstein-Barr virus-associated Hodgkin's disease with age. Leukemia 14, 748-753. https://doi.org/10.1038/sj.leu.2401724
  48. Forero-Torres, A., Leonard, J. P., Younes, A., Rosenblatt, J. D., Brice, P., Bartlett, N. L., Bosly, A., Pinter-Brown, L., Kennedy, D., Sievers, E. L. and Gopal, A. K. (2009) A Phase II study of SGN-30 (anti- CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br. J. Haematol. 146, 171-179. https://doi.org/10.1111/j.1365-2141.2009.07740.x
  49. Forte, E. and Luftig, M. A. (2011) The role of microRNAs in Epstein-Barr virus latency and lytic reactivation. Microbes Infect. [Epub ahead of print]
  50. Foss, H. D., Reusch, R., Demel, G., Lenz, G., Anagnostopoulos, I., Hummel, M. and Stein, H. (1999) Frequent expression of the Bcell- specifi c activator protein in Reed-Sternberg cells of classical Hodgkin's disease provides further evidence for its B-cell origin. Blood 94, 3108-3113.
  51. Friedberg, J. W., Neuberg, D., Kim, H., Miyata, S., McCauley, M., Fisher, D. C., Takvorian, T. and Canellos, G. P. (2003) Gemcitabine added to doxorubicin, bleomycin, and vinblastine for the treatment of de novo Hodgkin disease: unacceptable acute pulmonary toxicity. Cancer 98, 978-982. https://doi.org/10.1002/cncr.11582
  52. Friedrichs, C., Neyts, J., Gaspar, G., De Clercq, E. and Wutzler, P. (2004) Evaluation of antiviral activity against human herpesvirus 8 (HHV-8) and Epstein-Barr virus (EBV) by a quantitative real-time PCR assay. Antiviral Res. 62, 121-123. https://doi.org/10.1016/j.antiviral.2003.12.005
  53. Frisan, T., Sjoberg, J., Dolcetti, R., Boiocchi, M., De Re, V., Carbone, A., Brautbar, C., Battat, S., Biberfeld, P., Eckman, M. and et al. (1995) Local suppression of Epstein-Barr virus (EBV)-specifi c cytotoxicity in biopsies of EBV-positive Hodgkin's disease. Blood 86, 1493-1501.
  54. Gediya, L. K., Khandelwal, A., Patel, J., Belosay, A., Sabnis, G., Mehta, J., Purushottamachar, P. and Njar, V. C. (2008) Design, synthesis, and evaluation of novel mutual prodrugs (hybrid drugs) of all-transretinoic acid and histone deacetylase inhibitors with enhanced anticancer activities in breast and prostate cancer cells in vitro. J. Med. Chem. 51, 3895-3904. https://doi.org/10.1021/jm8001839
  55. Gershburg, E., Hong, K. and Pagano, J. S. (2004) Effects of maribavir and selected indolocarbazoles on Epstein-Barr virus protein kinase BGLF4 and on viral lytic replication. Antimicrob.Agents Chemother. 48, 1900-1903. https://doi.org/10.1128/AAC.48.5.1900-1903.2004
  56. Gershburg, E. and Pagano, J. S. (2002) Phosphorylation of the Epstein- Barr virus (EBV) DNA polymerase processivity factor EA-D by the EBV-encoded protein kinase and effects of the L-riboside benzimidazole 1263W94. J. Virol. 76, 998-1003. https://doi.org/10.1128/JVI.76.3.998-1003.2002
  57. Gires, O., Zimber-Strobl, U., Gonnella, R., Ueffi ng, M., Marschall, G., Zeidler, R., Pich, D. and Hammerschmidt, W. (1997) Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J. 16, 6131-6140. https://doi.org/10.1093/emboj/16.20.6131
  58. Glozak, M. A., Sengupta, N., Zhang, X. and Seto, E. (2005) Acetylation and deacetylation of non-histone proteins. Gene 363, 15-23. https://doi.org/10.1016/j.gene.2005.09.010
  59. Gottschalk, S., Edwards, O. L., Sili, U., Huls, M. H., Goltsova, T., Davis, A. R., Heslop, H. E. and Rooney, C. M. (2003) Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies. Blood 101, 1905-1912. https://doi.org/10.1182/blood-2002-05-1514
  60. Grasser, F. A., Murray, P. G., Kremmer, E., Klein, K., Remberger, K., Feiden, W., Reynolds, G., Niedobitek, G., Young, L. S. and Mueller- Lantzsch, N. (1994) Monoclonal antibodies directed against the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1): immunohistologic detection of EBNA1 in the malignant cells of Hodgkin's disease. Blood 84, 3792-3798.
  61. Gregorovic, G., Bosshard, R., Karstegl, C. E., White, R. E., Pattle, S., Chiang, A. K., Dittrich-Breiholz, O., Kracht, M., Russ, R. and Farrell, P. J. (2011) Cellular gene expression that correlates with EBER expression in Epstein-Barr Virus-infected lymphoblastoid cell lines. J. Virol. 85, 3535-3545. https://doi.org/10.1128/JVI.02086-10
  62. Gutensohn, N. and Cole, P. (1980) Epidemiology of Hodgkin's disease. Semin. Oncol. 7, 92-102.
  63. Hartline, C. B., Harden, E. A., Williams-Aziz, S. L., Kushner, N. L., Brideau, R. J. and Kern, E. R. (2005) Inhibition of herpesvirus replication by a series of 4-oxo-dihydroquinolines with viral polymerase activity. Antiviral Res. 65, 97-105. https://doi.org/10.1016/j.antiviral.2004.10.003
  64. Herbst, H., Dallenbach, F., Hummel, M., Niedobitek, G., Pileri, S., Muller-Lantzsch, N. and Stein, H. (1991) Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells. Proc. Natl. Acad. Sci. USA 88, 4766-4770. https://doi.org/10.1073/pnas.88.11.4766
  65. Herbst, H., Steinbrecher, E., Niedobitek, G., Young, L. S., Brooks, L., Muller-Lantzsch, N. and Stein, H. (1992) Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin's disease. Blood 80, 484-491.
  66. Ho, J. W., Liang, R. H. and Srivastava, G. (1999) Differential cytokine expression in EBV positive peripheral T cell lymphomas. Mol. Pathol. 52, 269-274. https://doi.org/10.1136/mp.52.5.269
  67. Hoppe, R. T., Horning, S. J., Hancock, S. L. and Rosenberg, S. A. (1989) Current Stanford clinical trials for Hodgkin's disease. Recent Results Cancer Res. 117, 182-190. https://doi.org/10.1007/978-3-642-83781-4_19
  68. Hoppe, R. T., Horning, S. J. and Rosenberg, S. A. (1985) The concept, evolution and preliminary results of the current Stanford clinical trials for Hodgkin's disease. Cancer Surv. 4, 459-475.
  69. Hsieh, D. J., Camiolo, S. M. and Yates, J. L. (1993) Constitutive binding of EBNA1 protein to the Epstein-Barr virus replication origin, oriP, with distortion of DNA structure during latent infection. EMBO J. 12, 4933-4944.
  70. Humme, S., Reisbach, G., Feederle, R., Delecluse, H. J., Bousset, K., Hammerschmidt, W. and Schepers, A. (2003) The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc. Natl. Acad. Sci. USA 100, 10989-10994. https://doi.org/10.1073/pnas.1832776100
  71. Hummel, M., Anagnostopoulos, I., Dallenbach, F., Korbjuhn, P., Dimmler, C. and Stein, H. (1992) EBV infection patterns in Hodgkin's disease and normal lymphoid tissue: expression and cellular localization of EBV gene products. Br. J. Haematol. 82, 689-694. https://doi.org/10.1111/j.1365-2141.1992.tb06945.x
  72. Iwakiri, D., Eizuru, Y., Tokunaga, M. and Takada, K. (2003) Autocrine growth of Epstein-Barr virus-positive gastric carcinoma cells mediated by an Epstein-Barr virus-encoded small RNA. Cancer Res. 63, 7062-7067.
  73. Iwakiri, D., Sheen, T. S., Chen, J. Y., Huang, D. P. and Takada, K. (2005) Epstein-Barr virus-encoded small RNA induces insulin-like growth factor 1 and supports growth of nasopharyngeal carcinomaderived cell lines. Oncogene 24, 1767-1773. https://doi.org/10.1038/sj.onc.1208357
  74. Iwakiri, D. and Takada, K. (2010) Role of EBERs in the pathogenesis of EBV infection. Adv. Cancer Res. 107, 119-136. https://doi.org/10.1016/S0065-230X(10)07004-1
  75. Iwakiri, D., Zhou, L., Samanta, M., Matsumoto, M., Ebihara, T., Seya, T., Imai, S., Fujieda, M., Kawa, K. and Takada, K. (2009) Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3. J. Exp. Med. 206, 2091-2099. https://doi.org/10.1084/jem.20081761
  76. Izumi, K. M. and Kieff, E. D. (1997) The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappaB. Proc. Natl. Acad. Sci. USA 94, 12592-12597. https://doi.org/10.1073/pnas.94.23.12592
  77. Jarrett, R. F., Stark, G. L., White, J., Angus, B., Alexander, F. E., Krajewski, A. S., Freeland, J., Taylor, G. M. and Taylor, P. R. (2005) Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defi ned subgroups of patients with classic Hodgkin lymphoma: a population-based study. Blood 106, 2444-2451. https://doi.org/10.1182/blood-2004-09-3759
  78. Jona, A., Khaskhely, N., Buglio, D., Shafer, J. A., Derenzini, E., Bollard, C. M., Medeiros, L. J., Illes, A., Ji, Y. and Younes, A. (2011) The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors. Exp. Hematol. [Epub ahead of print]
  79. Jundt, F., Raetzel, N., Muller, C., Calkhoven, C. F., Kley, K., Mathas, S., Lietz, A., Leutz, A. and Dorken, B. (2005) A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein b and NF-kB activity in Hodgkin and anaplastic large cell lymphomas. Blood 106, 1801-1807. https://doi.org/10.1182/blood-2004-11-4513
  80. Jung, D. and Dorr, A. (1999) Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J. Clin. Pharmacol. 39, 800-804. https://doi.org/10.1177/00912709922008452
  81. Kieff, E. (1996) Epstein-Barr virus and its replication. Lippincott-Raven Publishers, Philadelphia, PA.
  82. Kira, T., Grill, S. P., Dutschman, G. E., Lin, J. S., Qu, F., Choi, Y., Chu, C. K. and Cheng, Y. C. (2000) Anti-Epstein-Barr virus (EBV) activity of beta-L-5-iododioxolane uracil is dependent on EBV thymidine kinase. Antimicrob. Agents. Chemother. 44, 3278-3284. https://doi.org/10.1128/AAC.44.12.3278-3284.2000
  83. Kirschbaum, M. H., Goldman, B. H., Zain, J. M., Cook, J. R., Rimsza, L. M., Forman, S. J. and Fisher, R. I. (2011) A Phase 2 Study of Vorinostat for Treatment of Relapsed or Refractory Hodgkin Lymphoma: Southwest Oncology Group Study S0517. Leuk. Lymphoma. [Epub ahead of print]
  84. Kitagawa, N., Goto, M., Kurozumi, K., Maruo, S., Fukayama, M., Naoe, T., Yasukawa, M., Hino, K., Suzuki, T., Todo, S. and Takada, K. (2000) Epstein-Barr virus-encoded poly(A)(-) RNA supports Burkitt's lymphoma growth through interleukin-10 induction. EMBO J. 19, 6742-6750. https://doi.org/10.1093/emboj/19.24.6742
  85. Klimm, B., Schnell, R., Diehl, V. and Engert, A. (2005) Current treatment and immunotherapy of Hodgkin's lymphoma. Haematologica 90, 1680-1692.
  86. Komano, J., Maruo, S., Kurozumi, K., Oda, T. and Takada, K. (1999) Oncogenic role of Epstein-Barr virus-encoded RNAs in Burkitt's lymphoma cell line Akata. J. Virol. 73, 9827-9831.
  87. Kung, C. P., Meckes, D. G., Jr. and Raab-Traub, N. (2011) Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta. J. Virol. 85, 4399-4408. https://doi.org/10.1128/JVI.01703-10
  88. Kuppers, R. (2003) Somatic hypermutation and B cell receptor selection in normal and transformed human B cells. Ann. NY Acad. Sci. 987, 173-179. https://doi.org/10.1111/j.1749-6632.2003.tb06046.x
  89. Kuppers, R. (2009) Molecular biology of Hodgkin lymphoma. Hematology Am. Soc. Hematol. Educ. Program 491-496.
  90. Kuppers, R., Rajewsky, K., Zhao, M., Simons, G., Laumann, R., Fischer, R. and Hansmann, M. L. (1994) Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc. Natl. Acad. Sci. USA 91, 10962-10966. https://doi.org/10.1073/pnas.91.23.10962
  91. Lambert, S. L. and Martinez, O. M. (2007) Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J. Immunol. 179, 8225-8234. https://doi.org/10.4049/jimmunol.179.12.8225
  92. Lamprecht, B., Kreher, S., Anagnostopoulos, I., Johrens, K., Monteleone, G., Jundt, F., Stein, H., Janz, M., Dorken, B. and Mathas, S. (2008) Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha. Blood 112, 3339-3347. https://doi.org/10.1182/blood-2008-01-134783
  93. Law, C. L., Gordon, K. A., Collier, J., Klussman, K., McEarchern, J. A., Cerveny, C. G., Mixan, B. J., Lee, W. P., Lin, Z., Valdez, P., Wahl, A. F. and Grewal, I. S. (2005) Preclinical antilymphoma activity of a humanized anti-CD40 monoclonal antibody, SGN-40. Cancer Res. 65, 8331-8338. https://doi.org/10.1158/0008-5472.CAN-05-0095
  94. Lee, I. S., Kim, S. H., Song, H. G. and Park, S. H. (2003) The molecular basis for the generation of Hodgkin and Reed-Sternberg cells in Hodgkin's lymphoma. Int. J. Hematol. 77, 330-335. https://doi.org/10.1007/BF02982639
  95. Leoncini, L., Spina, D., Nyong'o, A., Abinya, O., Minacci, C., Disanto, A., De Luca, F., De Vivo, A., Sabattini, E., Poggi, S., Pileri, S. and Tosi, P. (1996) Neoplastic cells of Hodgkin's disease show differences in EBV expression between Kenya and Italy. Int. J. Cancer 65, 781-784. https://doi.org/10.1002/(SICI)1097-0215(19960315)65:6<781::AID-IJC13>3.0.CO;2-7
  96. Levine, P. H., Ablashi, D. V., Berard, C. W., Carbone, P. P., Waggoner, D. E. and Malan, L. (1971) Elevated antibody titers to Epstein-Barr virus in Hodgkin's disease. Cancer 27, 416-421. https://doi.org/10.1002/1097-0142(197102)27:2<416::AID-CNCR2820270227>3.0.CO;2-W
  97. Levitskaya, J., Coram, M., Levitsky, V., Imreh, S., Steigerwald-Mullen, P. M., Klein, G., Kurilla, M. G. and Masucci, M. G. (1995) Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375, 685-688. https://doi.org/10.1038/375685a0
  98. Levitskaya, J., Sharipo, A., Leonchiks, A., Ciechanover, A. and Masucci, M. G. (1997) Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein- Barr virus nuclear antigen 1. Proc. Natl. Acad. Sci. USA 94, 12616-12621. https://doi.org/10.1073/pnas.94.23.12616
  99. Longnecker, R. (2000) Epstein-Barr virus latency: LMP2, a regulator or means for Epstein-Barr virus persistence? Adv. Cancer Res. 79, 175-200. https://doi.org/10.1016/S0065-230X(00)79006-3
  100. Longnecker, R. and Kieff, E. (1990) A second Epstein-Barr virus membrane protein (LMP2) is expressed in latent infection and colocalizes with LMP1. J. Virol. 64, 2319-2326.
  101. Longo, D. L., Young, R. C., Wesley, M., Hubbard, S. M., Duffey, P. L., Jaffe, E. S. and DeVita, V. T., Jr. (1986) Twenty years of MOPP therapy for Hodgkin's disease. J. Clin. Oncol. 4, 1295-1306.
  102. Lu, J., Murakami, M., Verma, S. C., Cai, Q., Haldar, S., Kaul, R., Wasik, M. A., Middeldorp, J. and Robertson, E. S. (2011) Epstein-Barr Virus nuclear antigen 1 (EBNA1) confers resistance to apoptosis in EBV-positive B-lymphoma cells through up-regulation of survivin. Virology 410, 64-75. https://doi.org/10.1016/j.virol.2010.10.029
  103. Luqman, M., Klabunde, S., Lin, K., Georgakis, G. V., Cherukuri, A., Holash, J., Goldbeck, C., Xu, X., Kadel, E. E., 3rd, Lee, S. H., Aukerman, S. L., Jallal, B., Aziz, N., Weng, W. K., Wierda, W., O'Brien, S. and Younes, A. (2008) The antileukemia activity of a human anti- CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells. Blood 112, 711-720. https://doi.org/10.1182/blood-2007-04-084756
  104. Lutzky, V. P., Corban, M., Heslop, L., Morrison, L. E., Crooks, P., Hall, D. F., Coman, W. B., Thomson, S. A. and Moss, D. J. (2010) Novel approach to the formulation of an Epstein-Barr virus antigen-based nasopharyngeal carcinoma vaccine. J. Virol. 84, 407-417. https://doi.org/10.1128/JVI.01303-09
  105. Lynch, D. T., Zimmerman, J. S. and Rowe, D. T. (2002) Epstein-Barr virus latent membrane protein 2B (LMP2B) co-localizes with LMP2A in perinuclear regions in transiently transfected cells. J. Gen. Virol. 83, 1025-1035.
  106. Maggioncalda, A., Malik, N., Shenoy, P., Smith, M., Sinha, R. and Flowers, C. R. (2011) Clinical, molecular, and environmental risk factors for hodgkin lymphoma. Adv. Hematol. 2011, 736261.
  107. Marshall, N. A., Vickers, M. A. and Barker, R. N. (2003) Regulatory T cells secreting IL-10 dominate the immune response to EBV latent membrane protein 1. J. Immunol. 170, 6183-6189. https://doi.org/10.4049/jimmunol.170.12.6183
  108. Masucci, M. G., Zhang, Q. J., Gavioli, R., De Campos-Lima, P. O., Murray, R. J., Brooks, J., Griffi n, H., Ploegh, H. and Rickinson, A. B. (1992) Immune escape by Epstein-Barr virus (EBV) carrying Burkitt's lymphoma: in vitro reconstitution of sensitivity to EBVspecifi c cytotoxic T cells. Int. Immunol. 4, 1283-1292. https://doi.org/10.1093/intimm/4.11.1283
  109. Meyer, R. M., Ambinder, R. F. and Stroobants, S. (2004) Hodgkin's lymphoma: evolving concepts with implications for practice. Hematology Am. Soc. Hematol. Educ. Program 184-202.
  110. Minucci, S. and Pelicci, P. G. (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 6, 38-51. https://doi.org/10.1038/nrc1779
  111. Morrison, J. A., Klingelhutz, A. J. and Raab-Traub, N. (2003) Epstein-Barr virus latent membrane protein 2A activates beta-catenin signaling in epithelial cells. J. Virol. 77, 12276-12284. https://doi.org/10.1128/JVI.77.22.12276-12284.2003
  112. Murray, P. G., Young, L. S., Rowe, M. and Crocker, J. (1992) Immunohistochemical demonstration of the Epstein-Barr virus-encoded latent membrane protein in paraffi n sections of Hodgkin's disease. J. Pathol. 166, 1-5. https://doi.org/10.1002/path.1711660102
  113. Niedobitek, G., Kremmer, E., Herbst, H., Whitehead, L., Dawson, C. W., Niedobitek, E., von Ostau, C., Rooney, N., Grasser, F. A. and Young, L. S. (1997) Immunohistochemical detection of the Epstein- Barr virus-encoded latent membrane protein 2A in Hodgkin's disease and infectious mononucleosis. Blood 90, 1664-1672.
  114. O'Connor, O. A. (2005) Developing new drugs for the treatment of lymphoma. Eur. J. Haematol. 75, 150-158.
  115. Ofl azoglu, E., Kissler, K. M., Sievers, E. L., Grewal, I. S. and Gerber, H. P. (2008) Combination of the anti-CD30-auristatin-E antibody-drug conjugate (SGN-35) with chemotherapy improves antitumour activity in Hodgkin lymphoma. Br. J. Haematol. 142, 69-73. https://doi.org/10.1111/j.1365-2141.2008.07146.x
  116. Oki, Y. and Younes, A. (2010) Does rituximab have a place in treating classic hodgkin lymphoma? Curr. Hematol. Malig. Rep. 5, 135-139. https://doi.org/10.1007/s11899-010-0052-z
  117. Oza, A. M., Ganesan, T. S., Leahy, M., Gregory, W., Lim, J., Dadiotis, L., Barbounis, V., Jones, A. E., Amess, J., Stansfeld, A. G. and et al. (1993) Patterns of survival in patients with Hodgkin's disease: long follow up in a single centre. Ann. Oncol. 4, 385-392.
  118. Pagano, J. S. (1995) Antiviral Chemotherapy. John Wiley & Sons Ltd.
  119. Pagano, J. S., Sixbey, J. W. and Lin, J. C. (1983) Acyclovir and Epstein- Barr virus infection. J. Antimicrob. Chemother. 12, 113-121. https://doi.org/10.1093/jac/12.suppl_B.113
  120. Pallesen, G., Hamilton-Dutoit, S. J., Rowe, M. and Young, L. S. (1991) Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 337, 320-322. https://doi.org/10.1016/0140-6736(91)90943-J
  121. Pan, J., Zhang, Q., Zhou, J., Ma, D., Xiao, X. and Wang, D. W. (2009) Recombinant adeno-associated virus encoding Epstein-Barr virus latent membrane proteins fused with heat shock protein as a potential vaccine for nasopharyngeal carcinoma. Mol. Cancer Ther. 8, 2754-2761. https://doi.org/10.1158/1535-7163.MCT-08-1176
  122. Panousis, C. G. and Rowe, D. T. (1997) Epstein-Barr virus latent membrane protein 2 associates with and is a substrate for mitogen-activated protein kinase. J. Virol. 71, 4752-4760.
  123. Paramita, D. K., Fatmawati, C., Juwana, H., van Schaijk, F. G., Fachiroh, J., Haryana, S. M. and Middeldorp, J. M. (2011) Humoral immune responses to Epstein-Barr virus encoded tumor associated proteins and their putative extracellular domains in nasopharyngeal carcinoma patients and regional controls. J. Med. Virol. 83, 665-678. https://doi.org/10.1002/jmv.21960
  124. Pileri, S. A., Ascani, S., Leoncini, L., Sabattini, E., Zinzani, P. L., Piccaluga, P. P., Pileri, A. Jr., Giunti, M., Falini, B., Bolis, G. B. and Stein, H. (2002) Hodgkin's lymphoma: the pathologist's viewpoint. J. Clin. Pathol. 55, 162-176. https://doi.org/10.1136/jcp.55.3.162
  125. Pinkus, G. S., Lones, M., Shintaku, I. P. and Said, J. W. (1994) Immunohistochemical detection of Epstein-Barr virus-encoded latent membrane protein in Reed-Sternberg cells and variants of Hodgkin's disease. Mod. Pathol. 7, 454-461.
  126. Poppema, S., Delsol, G., Pileri, S. A., Stein, H., Swerdlow, S.H., Warnke, R. A. and Jaffe, E. S. (2008) Nodular lymphocyte predominant Hodgkin lymphoma. WHO Classifi cation of Tumours of the Haemotopoietic and Lymphoid Tissues. 323-325. IARC Press, Lyon.
  127. Poppema, S., Potters, M., Emmens, R., Visser, L. and van den Berg, A. (1999) Immune reactions in classical Hodgkin's lymphoma. Semin. Hematol. 36, 253-259.
  128. Purifoy, D. J., Beauchamp, L. M., de Miranda, P., Ertl, P., Lacey, S., Roberts, G., Rahim, S.G., Darby, G., Krenitsky, T.A. and Powell, K. L. (1993) Review of research leading to new anti-herpesvirus agents in clinical development: valaciclovir hydrochloride (256U, the L-valyl ester of acyclovir) and 882C, a specifi c agent for varicella zoster virus. J. Med. Virol. Suppl 1, 139-145.
  129. Reinstein, E. and Ciechanover, A. (2006) Narrative review: protein degradation and human diseases: the ubiquitin connection. Ann. Intern. Med. 145, 676-684. https://doi.org/10.7326/0003-4819-145-9-200611070-00010
  130. Rickinson, A. B., Gregory, C. D. and Young, L. S. (1987) Viruses and cancer risks: outgrowth of Epstein-Barr virus-positive Burkitt's lymphoma in the immune host. Med. Oncol. Tumor Pharmacother. 4, 177-186.
  131. Rickinson, A. B., Murray, R. J., Brooks, J., Griffi n, H., Moss, D. J. and Masucci, M. G. (1992) T cell recognition of Epstein-Barr virus associated lymphomas. Cancer Surv. 13, 53-80.
  132. Robak, T. (2008) Novel monoclonal antibodies for the treatment of chronic lymphocytic leukemia. Curr. Cancer Drug Targets 8, 156-171. https://doi.org/10.2174/156800908783769319
  133. Rosa, M. D., Gottlieb, E., Lerner, M. R. and Steitz, J. A. (1981) Striking similarities are exhibited by two small Epstein-Barr virus-encoded ribonucleic acids and the adenovirus-associated ribonucleic acids VAI and VAII. Mol. Cell Biol. 1, 785-796.
  134. Rowe, M., Rooney, C. M., Edwards, C. F., Lenoir, G. M. and Rickinson, A. B. (1986) Epstein-Barr virus status and tumour cell phenotype in sporadic Burkitt's lymphoma. Int. J. Cancer 37, 367-373. https://doi.org/10.1002/ijc.2910370307
  135. Samanta, M., Iwakiri, D., Kanda, T., Imaizumi, T. and Takada, K. (2006) EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN. EMBO J. 25, 4207-4214. https://doi.org/10.1038/sj.emboj.7601314
  136. Samanta, M., Iwakiri, D. and Takada, K. (2008) Epstein-Barr virusencoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling. Oncogene 27, 4150-4160. https://doi.org/10.1038/onc.2008.75
  137. Scholle, F., Bendt, K. M. and Raab-Traub, N. (2000) Epstein-Barr virus LMP2A transforms epithelial cells, inhibits cell differentiation, and activates Akt. J. Virol. 74, 10681-10689. https://doi.org/10.1128/JVI.74.22.10681-10689.2000
  138. Shah, K. M., Stewart, S. E., Wei, W., Woodman, C. B., O'Neil, J. D., Dawson, C. W. and Young, L. S. (2009) The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation. Oncogene 28, 3903-3914. https://doi.org/10.1038/onc.2009.249
  139. Shah, K. M. and Young, L. S. (2009) Epstein-Barr virus and carcinogenesis: beyond Burkitt's lymphoma. Clin. Microbiol. Infect. 15, 982-988. https://doi.org/10.1111/j.1469-0691.2009.03033.x
  140. Shimabukuro-Vornhagen, A., Haverkamp, H., Engert, A., Balleisen, L., Majunke, P., Heil, G., Eich, H. T., Stein, H., Diehl, V. and Josting, A. (2005) Lymphocyte-rich classical Hodgkin's lymphoma: clinical presentation and treatment outcome in 100 patients treated within German Hodgkin's Study Group trials. J. Clin. Oncol. 23, 5739-5745. https://doi.org/10.1200/JCO.2005.17.970
  141. Sing, A. P., Ambinder, R. F., Hong, D. J., Jensen, M., Batten, W., Petersdorf, E. and Greenberg, P. D. (1997) Isolation of Epstein-Barr virus (EBV)-specifi c cytotoxic T lymphocytes that lyse Reed-Sternberg cells: implications for immune-mediated therapy of EBV+ Hodgkin's disease. Blood 89, 1978-1986.
  142. Slack, G. W., Ferry, J. A., Hasserjian, R. P., Sohani, A. R., Longtine, J. A., Harris, N. L. and Zukerberg, L. R. (2009) Lymphocyte depleted Hodgkin lymphoma: an evaluation with immunophenotyping and genetic analysis. Leuk. Lymphoma 50, 937-943. https://doi.org/10.1080/10428190902930488
  143. Smith, C., Cooper, L., Burgess, M., Rist, M., Webb, N., Lambley, E., Tellam, J., Marlton, P., Seymour, J. F., Gandhi, M. and Khanna, R. (2006) Functional reversion of antigen-specifi c CD8+ T cells from patients with Hodgkin lymphoma following in vitro stimulation with recombinant polyepitope. J. Immunol. 177, 4897-4906. https://doi.org/10.4049/jimmunol.177.7.4897
  144. Specht, L., Gray, R. G., Clarke, M. J. and Peto, R. (1998) Infl uence of more extensive radiotherapy and adjuvant chemotherapy on longterm outcome of early-stage Hodgkin's disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin's Disease Collaborative Group. J. Clin. Oncol. 16, 830-843.
  145. Spitz, M. R., Sider, J. G., Johnson, C. C., Butler, J. J., Pollack, E. S. and Newell, G. R. (1986) Ethnic patterns of Hodgkin's disease incidence among children and adolescents in the United States, 1973-82. J. Natl. Cancer Inst. 76, 235-239.
  146. Stark, G. L., Wood, K. M., Jack, F., Angus, B., Proctor, S. J. and Taylor, P. R. (2002) Hodgkin's disease in the elderly: a population-based study. Br. J. Haematol. 119, 432-440. https://doi.org/10.1046/j.1365-2141.2002.03815.x
  147. Steven, N. M., Leese, A. M., Annels, N. E., Lee, S. P. and Rickinson, A. B. (1996) Epitope focusing in the primary cytotoxic T cell response to Epstein-Barr virus and its relationship to T cell memory. J. Exp. Med. 184, 1801-1813. https://doi.org/10.1084/jem.184.5.1801
  148. Straus, D. J., Johnson, J. L., LaCasce, A. S., Bartlett, N. L., Kostakoglu, L., Hsi, E. D., Schoder, H., Hall, N. C., Jung, S. H., Canellos, G. P., Schwartz, L. H., Takvorian, R. W., Juweid, M. E. and Cheson, B.D. (2011) Doxorubicin, vinblastine, and gemcitabine (CALGB 50203) for stage I/II nonbulky Hodgkin lymphoma: pretreatment prognostic factors and interim PET. Blood 117, 5314-5320. https://doi.org/10.1182/blood-2010-10-314260
  149. Su, Z., Peluso, M. V., Raffegerst, S. H., Schendel, D. J. and Roskrow, M. A. (2001) The generation of LMP2a-specifi c cytotoxic T lymphocytes for the treatment of patients with Epstein-Barr virus-positive Hodgkin disease. Eur. J. Immunol. 31, 947-958. https://doi.org/10.1002/1521-4141(200103)31:3<947::AID-IMMU947>3.0.CO;2-M
  150. Swaminathan, S., Tomkinson, B. and Kieff, E. (1991) Recombinant Epstein-Barr virus with small RNA (EBER) genes deleted transforms lymphocytes and replicates in vitro. Proc. Natl. Acad. Sci. USA 88, 1546-1550. https://doi.org/10.1073/pnas.88.4.1546
  151. Tarasenko, N., Nudelman, A., Tarasenko, I., Entin-Meer, M., Hass-Kogan, D., Inbal, A. and Rephaeli, A. (2008) Histone deacetylase inhibitors: the anticancer, antimetastatic and antiangiogenic activities of AN-7 are superior to those of the clinically tested AN-9 (Pivanex). Clin. Exp. Metastasis 25, 703-716. https://doi.org/10.1007/s10585-008-9179-x
  152. Taylor, G. S., Haigh, T. A., Gudgeon, N. H., Phelps, R. J., Lee, S. P., Steven, N. M. and Rickinson, A. B. (2004) Dual stimulation of Epstein- Barr Virus (EBV)-specifi c CD4+- and CD8+-T-cell responses by a chimeric antigen construct: potential therapeutic vaccine for EBV-positive nasopharyngeal carcinoma. J. Virol. 78, 768-778. https://doi.org/10.1128/JVI.78.2.768-778.2004
  153. Tellam, J., Connolly, G., Webb, N., Duraiswamy, J. and Khanna, R. (2003) Proteasomal targeting of a viral oncogene abrogates oncogenic phenotype and enhances immunogenicity. Blood 102, 4535-4540. https://doi.org/10.1182/blood-2003-03-0870
  154. Tellam, J., Sherritt, M., Thomson, S., Tellam, R., Moss, D. J., Burrows, S. R., Wiertz, E. and Khanna, R. (2001) Targeting of EBNA1 for rapid intracellular degradation overrides the inhibitory effects of the Gly-Ala repeat domain and restores CD8+ T cell recognition. J. Biol. Chem. 276, 33353-33360. https://doi.org/10.1074/jbc.M104535200
  155. Thomas, R. K., Re, D., Wolf, J. and Diehl, V. (2004) Part I: Hodgkin's lymphoma--molecular biology of Hodgkin and Reed-Sternberg cells. Lancet Oncol. 5, 11-18. https://doi.org/10.1016/S1470-2045(03)01319-6
  156. Thompson, L. D., Fisher, S. I., Chu, W. S., Nelson, A. and Abbondanzo, S. L. (2004) HIV-associated Hodgkin lymphoma: a clinicopathologic and immunophenotypic study of 45 cases. Am. J. Clin. Pathol. 121, 727-738. https://doi.org/10.1309/PNVQ0PQGXHVY6L7G
  157. Timms, J. M., Bell, A., Flavell, J. R., Murray, P. G., Rickinson, A. B., Traverse-Glehen, A., Berger, F. and Delecluse, H. J. (2003) Target cells of Epstein-Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin's lymphoma. Lancet 361, 217-223. https://doi.org/10.1016/S0140-6736(03)12271-4
  158. Tobery, T. and Siliciano, R. F. (1999) Cutting edge: induction of enhanced CTL-dependent protective immunity in vivo by N-end rule targeting of a model tumor antigen. J. Immunol. 162, 639-642.
  159. van der Horst, C., Joncas, J., Ahronheim, G., Gustafson, N., Stein, G., Gurwith, M., Fleisher, G., Sullivan, J., Sixbey, J., Roland, S. and et al. (1991) Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis. J. Infect. Dis. 164, 788-792. https://doi.org/10.1093/infdis/164.4.788
  160. Varshavsky, A. (1996) The N-end rule: functions, mysteries, uses. Proc. Natl. Acad. Sci. USA 93, 12142-12149. https://doi.org/10.1073/pnas.93.22.12142
  161. Weinreb, M., Day, P. J., Niggli, F., Green, E. K., Nyong'o, A. O., Othieno- Abinya, N. A., Riyat, M. S., Raafat, F. and Mann, J. R. (1996) The consistent association between Epstein-Barr virus and Hodgkin's disease in children in Kenya. Blood 87, 3828-3836.
  162. Weiss, L. M., Chan, J. K. C., MacLennan, K. and Warnke, R. A. (1999) Pathology of classical Hodgkin's disease. Lippincott Williams & Wilkins, Philadelphia, PA.
  163. Weiss, L. M., Chen, Y. Y., Liu, X. F. and Shibata, D. (1991) Epstein-Barr virus and Hodgkin's disease. A correlative in situ hybridization and polymerase chain reaction study. Am. J. Pathol. 139, 1259-1265.
  164. Weiss, L. M., Movahed, L. A., Warnke, R. A. and Sklar, J. (1989) Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin's disease. N. Engl. J. Med. 320, 502-506. https://doi.org/10.1056/NEJM198902233200806
  165. Westphal, E. M., Blackstock, W., Feng, W., Israel, B. and Kenney, S. C. (2000) Activation of lytic Epstein-Barr virus (EBV) infection by radiation and sodium butyrate in vitro and in vivo: a potential method for treating EBV-positive malignancies. Cancer Res. 60, 5781-5788.
  166. Yajima, Y., Tanaka, A. and Nonoyama, M. (1976) Inhibition of productive replication of Epstein-Barr virus DNA by phosphonoacetic acid. Virology 71, 352-354. https://doi.org/10.1016/0042-6822(76)90119-7
  167. Yamamoto, N., Takizawa, T., Iwanaga, Y. and Shimizu, N. (2000) Malignant transformation of B lymphoma cell line BJAB by Epstein-Barr virus-encoded small RNAs. FEBS Lett. 484, 153-158. https://doi.org/10.1016/S0014-5793(00)02145-1
  168. Yee, K. W., Zeng, Z., Konopleva, M., Verstovsek, S., Ravandi, F., Ferrajoli, A., Thomas, D., Wierda, W., Apostolidou, E., Albitar, M., O'Brien, S., Andreeff, M. and Giles, F. J. (2006) Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 12, 5165-5173. https://doi.org/10.1158/1078-0432.CCR-06-0764
  169. Yoshioka, M., Kikuta, H., Ishiguro, N., Ma, X. and Kobayashi, K. (2003) Unique Epstein-Barr virus (EBV) latent gene expression, EBNA promoter usage and EBNA promoter methylation status in chronic active EBV infection. J. Gen. Virol. 84, 1133-1140. https://doi.org/10.1099/vir.0.18777-0
  170. Younes, A. (2009) Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology Am. Soc. Hematol. Educ. Program 507-519.
  171. Younes, A., Garg, A. and Aggarwal, B. B. (2003) Nuclear transcription factor-kappaB in Hodgkin's disease. Leuk. Lymphoma 44, 929-935. https://doi.org/10.1080/1042819031000067558
  172. Young, L.S. and Rickinson, A.B. (2004). Epstein-Barr virus: 40 years on. Nat. Rev. Cancer 4, 757-768. https://doi.org/10.1038/nrc1452
  173. Zacny, V. L., Gershburg, E., Davis, M. G., Biron, K. K. and Pagano, J. S. (1999) Inhibition of Epstein-Barr virus replication by a benzimidazole L-riboside: novel antiviral mechanism of 5, 6-dichloro-2- (isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole. J. Virol. 73, 7271-7277.
  174. Zheng, B., Fiumara, P., Li, Y. V., Georgakis, G., Snell, V., Younes, M., Vauthey, J. N., Carbone, A. and Younes, A. (2003) MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. Blood 102, 1019-1027. https://doi.org/10.1182/blood-2002-11-3507
  175. Zheng, B., Georgakis, G. V., Li, Y., Bharti, A., McConkey, D., Aggarwal, B. B. and Younes, A. (2004) Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-kappaB mutations or activation of the CD30, CD40, and RANK receptors. Clin. Cancer Res. 10, 3207-3215. https://doi.org/10.1158/1078-0432.CCR-03-0494