Abstract
Chromosomal translocations and somatic mutations occurring in the 5′ noncoding region of the BCL6 gene, encoding a transcriptional repressor, are most frequent genetic abnormalities associated with non-Hodgkin B-cell lymphoma and result in deregulated expression of BCL6. However, the significance of deregulated expression of BCL6 in lymphomagenesis and its effect on clinical outcomes of lymphoma patients have remained elusive. In the present study, we established Daudi and Raji B-cell lymphoma cell lines that overexpress BCL6 or its mutant, BCL6-Ala333/343, in which serine residues required for degradation through the proteasome pathway in B-cell receptor-stimulated cells are mutated. BCL6 overexpression did not have any significant effect on cell proliferation, but significantly inhibited apoptosis caused by etoposide, which induced a proteasome-dependent degradation of BCL6. BCL6-Ala333/343 was not degraded after etoposide treatment and strongly inhibited apoptosis. In these lymphoma cell lines, etoposide increased the generation of reactive oxygen species (ROS) and reduced mitochondria membrane potential, both of which were inhibited by the antioxidant N-acetyl-L-cysteine (NAC). NAC also inhibited apoptosis. Furthermore, BCL6 overexpression was found to inhibit the increase in ROS levels and apoptosis in response to etoposide and other chemotherapeutic reagents. These results raise the possibility that deregulated expression of BCL6 may endow lymphoma cells with resistance to chemotherapeutic reagents, most likely by enhancing the antioxidant defense systems.
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References
Albagli O, Lantoine D, Quief S, Quignon F, Englert C, Kerckaert JP, Montarras D, Pinset C and Lindon C . (1999). Oncogene, 18, 5063–5075.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson Jr J, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byd JC, Botstein D, Brown PO and Staudt LM . (2000). Nature, 403, 503–511.
Allman D, Jain A, Dent A, Maile RR, Selvaggi T, Kehry MR and Staudt LM . (1996). Blood, 87, 5257–5268.
Barrans SL, O'Connor SJ, Evans PA, Davies FE, Owen RG, Haynes AP, Morgan GJ and Jack AS . (2002). Br. J. Haematol., 117, 322–332.
Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A, Pezzella F, Fruchart C, Duval C, Monconduit M and Tilly H . (1994). Blood, 83, 2423–2427.
Bereshchenko OR, Gu W and Dalla-Favera R . (2002). Nat. Genet., 32, 606–613.
Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, Falini B, Louie DC, Offit K, Chaganti RS and Dalla-Favera R . (1995). Blood, 86, 45–53.
Chabner BA and Longo DL (eds) (2001). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams and Wilkins: Philadelphia.
Chen W, Iida S, Louie DC, Dalla-Favera R and Chaganti RS . (1998). Blood, 91, 603–607.
Dent AL, Shaffer AL, Yu X, Allman D and Staudt LM . (1997). Science, 276, 589–592.
Dent AL, Vasanwala FH and Toney LM . (2002). Crit. Rev. Oncol. Hematol., 41, 1–9.
Dvorakova K, Waltmire CN, Payne CM, Tome ME, Briehl MM and Dorr RT . (2001). Blood, 97, 3544–3551.
Fleury C, Mignotte B and Vayssiere JL . (2002). Biochimie, 84, 131–141.
Fukuda T, Yoshida T, Okada S, Hatano M, Miki T, Ishibashi K, Okabe S, Koseki H, Hirosawa S, Taniguchi M, Miyasaka N and Tokuhisa T . (1997). J. Exp. Med., 186, 439–448.
Jabs T . (1999). Biochem Pharmacol, 57, 231–245.
Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G and Bastard C . (1993). Nat. Genet., 5, 66–70.
Kikuchi M, Miki T, Kumagai T, Fukuda T, Kamiyama R, Miyasaka N and Hirosawa S . (2000). Oncogene, 19, 4941–4945.
Kojima S, Hatano M, Okada S, Fukuda T, Toyama Y, Yuasa S, Ito H and Tokuhisa T . (2001). Development, 128, 57–65.
Kumagai T, Miki T, Kikuchi M, Fukuda T, Miyasaka N, Kamiyama R and Hirosawa S . (1999). Oncogene, 18, 467–475.
Lo Coco F, Ye BH, Lista F, Corradini P, Offit K, Knowles DM, Chaganti RS and Dalla-Favera R . (1994). Blood, 83, 1757–1759.
Lossos IS, Jones CD, Warnke R, Natkunam Y, Kaizer H, Zehnder JL, Tibshirani R and Levy R . (2001). Blood, 98, 945–951.
Miki T, Kawamata N, Hirosawa S and Aoki N . (1994). Blood, 83, 26–32.
Nakamura Y . (2000). Leuk. Lymphoma, 38, 505–512.
Niu H . (2002). Hematol. Oncol., 20, 155–166.
Niu H, Ye BH and Dalla-Favera R . (1998). Genes Dev., 12, 1953–1961.
Ohno H and Fukuhara S . (1997). Leuk. Lymphoma, 27, 53–63.
Onizuka T, Moriyama M, Yamochi T, Kuroda T, Kazama A, Kanazawa N, Sato K, Kato T, Ota H and Mori S . (1995). Blood, 86, 28–37.
Otsuki T, Yano T, Clark HM, Bastard C, Kerckaert JP, Jaffe ES and Raffeld M . (1995). Blood, 85, 2877–2884.
Rothe G and Valet G . (1990). J. Leukoc. Biol., 47, 440–448.
Shaffer AL, Rosenwald A, Hurt EM, Giltnane JM, Lam LT, Pickeral OK and Staudt LM . (2001). Immunity, 15, 375–385.
Shaffer AL, Yu X, He Y, Boldrick J, Chan EP and Staudt LM . (2000). Immunity, 13, 199–212.
Tang TT, Dowbenko D, Jackson A, Toney L, Lewin DA, Dent AL and Lasky LA . (2002). J. Biol. Chem., 277, 14255–14265.
Wang X, Li Z, Naganuma A and Ye BH . (2002). Proc. Natl. Acad. Sci. USA, 99, 15018–15023.
Yamochi T, Kaneita Y, Akiyama T, Mori S and Moriyama M . (1999). Oncogene, 18, 487–494.
Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, Leung C, Nouri-Shirazi M, Orazi A, Chaganti RS, Rothman P, Stall AM, Pandolfi PP and Dalla-Favera R . (1997). Nat. Genet., 16, 161–170.
Ye BH, Chaganti S, Chang CC, Niu H, Corradini P, Chaganti RS and Dalla-Favera R . (1995). EMBO J., 14, 6209–6217.
Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS and Dalla-Favera R . (1993). Science, 262, 747–750.
Yee JK, Miyanohara A, LaPorte P, Bouic K, Burns JC and Friedmann T . (1994). Proc. Natl. Acad. Sci. USA, 91, 9564–9568.
Zamzami N and Kroemer G . (2001). Nat. Rev. Mol. Cell Biol., 2, 67–71.
Acknowledgements
We are grateful to Drs Shoji Yamaoka, Jun-ichi Miyazaki, Jane C Burns, Theodore Friedmann for the generous gifts of experimental materials. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan.
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Kurosu, T., Fukuda, T., Miki, T. et al. BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells. Oncogene 22, 4459–4468 (2003). https://doi.org/10.1038/sj.onc.1206755
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DOI: https://doi.org/10.1038/sj.onc.1206755
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