1. RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma
- Author
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Ben M. Parsons, Ganiraju C. Manyam, Miguel A. Piris, Jooryung Huh, Govind Bhagat, Carlo Visco, Jing Wang, Andrés J.M. Ferreri, Santiago Montes-Moreno, April Chiu, Ling Li, William W.L. Choi, Zijun Y. Xu-Monette, Alexandar Tzankov, L. Jeffrey Medeiros, Eric D. Hsi, Michael Boe Møller, Kristy L. Richards, Youli Zu, Mingzhi Zhang, Karen Dybkær, Maurilio Ponzoni, J. Han van Krieken, Lan V. Pham, Ken H. Young, Jane N. Winter, Attilio Orazi, Zhang, M., Xu-Monette, Z. Y., Li, L., Manyam, G. C., Visco, C., Tzankov, A., Wang, J., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K. L., Hsi, E. D., Choi, W. W., van Krieken, J. H., Huh, J., Ponzoni, M., Ferreri, A. J. M., Moller, M. B., Parsons, B. M., Winter, J. N., Piris, M. A., Medeiros, L. J., Pham, L. V., and Young, K. H.
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0301 basic medicine ,Male ,GCB ,NF-κB ,TP53 ,diffuse large B-cell lymphoma ,gene expression profiling ,p65 ,proteasome inhibitor ,Aged ,B-Lymphocytes ,Cell Line, Tumor ,Female ,Gene Expression Profiling ,Gene Expression Regulation, Neoplastic ,Humans ,Lymphoma, Large B-Cell, Diffuse ,Middle Aged ,NF-kappa B ,Signal Transduction ,Transcription Factor RelA ,Aging ,P65 ,Lymphoma ,0302 clinical medicine ,hemic and lymphatic diseases ,Proteasome inhibitor ,NF-kB ,Tumor ,Diffuse large B-cell lymphoma ,Diffuse ,3. Good health ,030220 oncology & carcinogenesis ,medicine.drug ,Research Paper ,Biology ,Cell Line ,03 medical and health sciences ,Large B-Cell ,medicine ,Neoplastic ,Cell growth ,Germinal center ,Cell Biology ,medicine.disease ,NFKB1 ,Gene expression profiling ,030104 developmental biology ,Gene Expression Regulation ,Cancer research - Abstract
It has been well established that nuclear factor kappa-B (NF-κB) activation is important for tumor cell growth and survival. RelA/p65 and p50 are the most common NF-kB subunits and involved in the classical NF-kB pathway. However, the prognostic and biological significance of RelA/p65 is equivocal in the field. In this study, we assessed RelA/p65 nuclear expression by immunohistochemistry in 487 patients with de novo diffuse large B-cell lymphoma (DLBCL), and studied the effects of molecular and pharmacological inhibition of NF-kB on cell viability. We found RelA/p65 nuclear expression, without associations with other apparent genetic or phenotypic abnormalities, had unfavorable prognostic impact in patients with stage I/II DLBCL. Gene expression profiling analysis suggested immune dysregulation and antiapoptosis may be relevant for the poorer prognosis associated with p65 hyperactivation in germinal center B-cell-like (GCB) DLBCL and in activated B-cell-like (ABC) DLBCL, respectively. We knocked down individual NF-κB subunits in representative DLBCL cells in vitro, and found targeting p65 was more effective than targeting other NF-κB subunits in inhibiting cell growth and survival. In summary, RelA/p65 nuclear overexpression correlates with significant poor survival in early-stage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-κB hyperactivation.
- Published
- 2016
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