RelA NF-kB subunit activation as a therapeutic target in diffuse large B-cell lymphoma

Mingzhi Zhang*, Zijun Y. Xu-Monette, Ling Li, Ganiraju C. Manyam, Carlo Visco, Alexandar Tzankov, Jing Wang, Santiago Montes-Moreno, Karen Dybkaer, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W.L. Choi, J. Han van Krieken, Jooryung Huh, Maurilio Ponzoni, Andrés J.M. FerreriMichael B. Møller, Ben M. Parsons, Jane N. Winter, Miguel A. Piris, L. Jeffrey Medeiros, Lan V. Pham, Ken H. Young

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Scopus citations

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-κB subunits and involved in the classical NF-κB 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-κB 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 expressionprofiling 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 Bcell- 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 earlystage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-κB hyperactivation.

Original languageEnglish (US)
Pages (from-to)3321-3340
Number of pages20
JournalAging
Volume8
Issue number12
DOIs
StatePublished - Jan 1 2016

Keywords

  • Diffuse large B-cell lymphoma
  • GCB
  • Gene expression profiling
  • NF-kB
  • P65
  • Proteasome inhibitor
  • TP53

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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    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. L., van Krieken, J. H., Huh, J., Ponzoni, M., ... Young, K. H. (2016). RelA NF-kB subunit activation as a therapeutic target in diffuse large B-cell lymphoma. Aging, 8(12), 3321-3340. https://doi.org/10.18632/aging.101121