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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zhang, M; Xu-Monette, ZY; Li, L; Manyam, GC; Visco, C; Tzankov, A; Wang, J; Montes-Moreno, S; Dybkaer, K; Chiu, A; Orazi, A; Zu, Y; Bhagat, G; Richards, KL; Hsi, ED; Choi, WWL; Han van Krieken, J; Huh, J; Ponzoni, M; Ferreri, AJM; Møller, MB; Parsons, BM; Winter, JN; Piris, MA; Medeiros, LJ; Pham, LV; Young, KH

Published Date

  • December 8, 2016

Published In

Volume / Issue

  • 8 / 12

Start / End Page

  • 3321 - 3340

PubMed ID

  • 27941215

Pubmed Central ID

  • 27941215

Electronic International Standard Serial Number (EISSN)

  • 1945-4589

Digital Object Identifier (DOI)

  • 10.18632/aging.101121

Language

  • eng

Conference Location

  • United States