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BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells

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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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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Correspondence to Osamu Miura.

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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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