EBV and Burkitt's Lymphoma
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《新英格兰医药杂志》
To the Editor: In their review of the persistence of the Epstein–Barr virus (EBV) and the origins of associated lymphomas (March 25 issue),1 Thorley-Lawson and Gross state, "There is no satisfactory explanation of how EBV participates in the pathogenesis of Burkitt's lymphoma." However, recently, Niller and colleagues proposed a new model for the development of Burkitt's lymphoma.2 In their model, a central role is played by the EBV-encoded RNA (EBER) locus of the EBV genome, the product of which has been implicated in EBV-related tumorigenesis, mainly by inhibiting apoptosis.3 The authors based their hypothesis on a binding site for c-Myc in the promoter region of EBER. They proposed that in an EBV-infected B cell (a type I latency cell expressing EBV nuclear antigen 1 and EBER) undergoing the germinal-center reaction, a translocated and deregulated c-Myc directly up-regulates the antiapoptotic EBER-transcription units.4 In this way, the balance between apoptosis and antiapoptosis (sustained by c-Myc and EBER, respectively) would be permanently shifted in favor of cell survival, allowing c-Myc to express its oncogenic potential and drive lymphomagenesis in the EBV-infected cell.5
Gabriele Rossi, M.D.
University of Pavia
27100 Pavia, Italy
gab.rossi@tiscali.it
Federico Bonetti, M.D.
IRCCS Policlinico San Matteo
27100 Pavia, Italy
References
Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 2004;350:1328-1337.
Niller HH, Salamon D, Ilg K, et al. EBV-associated neoplasm: alternative pathogenetic pathways. Med Hypotheses 2004;62:387-391.
Takada K, Nanbo A. The role of EBERs in oncogenesis. Semin Cancer Biol 2001;11:461-467.
Niller HH, Salamon D, Ilg K, et al. The in vivo binding site for oncoprotein c-Myc in the promoter for Epstein-Barr virus (EBV) encoding RNA (EBER) 1 suggests a specific role for EBV in lymphomagenesis. Med Sci Monit 2003;9:1-9.
Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 2002;109:321-334.
Dr. Thorley-Lawson replies: Rossi and Bonetti offer an interesting explanation of the role of EBV in the pathogenesis of Burkitt's lymphoma. However, what they describe is one scenario among several, all of which lack compelling evidence. This further illustrates our point that no satisfactory explanation of the involvement of EBV in Burkitt's lymphoma has been presented for which there is convincing evidence that is broadly accepted by the scientific community. In comparison, c-Myc is a risk factor for Burkitt's lymphoma that meets this standard. It is widely accepted to have a role in Burkitt's lymphoma, because it is known to regulate cell growth and apoptosis1 and is always translocated and deregulated in Burkitt's lymphoma.2,3 Furthermore, there is ample evidence (e.g., from mouse transgenics) that deregulated c-Myc contributes directly to the development of B-cell lymphomas, including Burkitt's lymphoma.4,5 Unlike c-Myc, all models of EBV involvement in Burkitt's lymphoma to date lack such overwhelming evidence. The scenario of Rossi and Bonetti may one day achieve the credibility of a satisfactory explanation, but we would not bet the house on it.
David A. Thorley-Lawson, Ph.D.
Tufts University School of Medicine
Boston, MA 02111
david.thorley-lawson@tufts.edu
References
Nilsson JA, Cleveland JL. Myc pathways provoking cell suicide and cancer. Oncogene 2003;22:9007-9021.
Taub R, Kirsch I, Morton C, et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A 1982;79:7837-7841.
Manolov G, Manolova Y. Marker band in one chromosome 14 from Burkitt lymphomas. Nature 1972;237:33-34.
Kovalchuk AL, Qi CF, Torrey TA, et al. Burkitt lymphoma in the mouse. J Exp Med 2000;192:1183-1190.
Adams JM, Harris AW, Pinkert CA, et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 1985;318:533-538.
Gabriele Rossi, M.D.
University of Pavia
27100 Pavia, Italy
gab.rossi@tiscali.it
Federico Bonetti, M.D.
IRCCS Policlinico San Matteo
27100 Pavia, Italy
References
Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 2004;350:1328-1337.
Niller HH, Salamon D, Ilg K, et al. EBV-associated neoplasm: alternative pathogenetic pathways. Med Hypotheses 2004;62:387-391.
Takada K, Nanbo A. The role of EBERs in oncogenesis. Semin Cancer Biol 2001;11:461-467.
Niller HH, Salamon D, Ilg K, et al. The in vivo binding site for oncoprotein c-Myc in the promoter for Epstein-Barr virus (EBV) encoding RNA (EBER) 1 suggests a specific role for EBV in lymphomagenesis. Med Sci Monit 2003;9:1-9.
Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 2002;109:321-334.
Dr. Thorley-Lawson replies: Rossi and Bonetti offer an interesting explanation of the role of EBV in the pathogenesis of Burkitt's lymphoma. However, what they describe is one scenario among several, all of which lack compelling evidence. This further illustrates our point that no satisfactory explanation of the involvement of EBV in Burkitt's lymphoma has been presented for which there is convincing evidence that is broadly accepted by the scientific community. In comparison, c-Myc is a risk factor for Burkitt's lymphoma that meets this standard. It is widely accepted to have a role in Burkitt's lymphoma, because it is known to regulate cell growth and apoptosis1 and is always translocated and deregulated in Burkitt's lymphoma.2,3 Furthermore, there is ample evidence (e.g., from mouse transgenics) that deregulated c-Myc contributes directly to the development of B-cell lymphomas, including Burkitt's lymphoma.4,5 Unlike c-Myc, all models of EBV involvement in Burkitt's lymphoma to date lack such overwhelming evidence. The scenario of Rossi and Bonetti may one day achieve the credibility of a satisfactory explanation, but we would not bet the house on it.
David A. Thorley-Lawson, Ph.D.
Tufts University School of Medicine
Boston, MA 02111
david.thorley-lawson@tufts.edu
References
Nilsson JA, Cleveland JL. Myc pathways provoking cell suicide and cancer. Oncogene 2003;22:9007-9021.
Taub R, Kirsch I, Morton C, et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A 1982;79:7837-7841.
Manolov G, Manolova Y. Marker band in one chromosome 14 from Burkitt lymphomas. Nature 1972;237:33-34.
Kovalchuk AL, Qi CF, Torrey TA, et al. Burkitt lymphoma in the mouse. J Exp Med 2000;192:1183-1190.
Adams JM, Harris AW, Pinkert CA, et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 1985;318:533-538.