Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma

Ling Li*, Zijun Y. Xu-Monette, Chi Young Ok, Alexandar Tzankov, Ganiraju C. Manyam, Ruifang Sun, Carlo Visco, Mingzhi Zhang, 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 PonzoniAndrés J.M. Ferreri, Michael B. Møller, Jinfen Wang, Ben M. Parsons, Jane N. Winter, Miguel A. Piris, Lan V. Pham, L. Jeffrey Medeiros, Ken H. Young

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Dysregulated NF-κB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-κB activation in diffuse large B-cell lymphoma (DLBCL) have not been well studied. In this study we analyzed the prognostic significance and gene-expression signature of c-Rel nuclear expression as surrogate of c-Rel activation in 460 patients with de novo DLBCL. Nuclear c-Rel expression, observed in 137 (26.3%) DLBCL patients frequently associated with extranoal origin, did not show significantly prognostic impact in the overall- or germinal center B-like-DLBCL cohort, likely due to decreased pAKT and Myc levels, up-regulation of FOXP3, FOXO3, MEG3 and other tumor suppressors coincided with c-Rel nuclear expression, as well as the complicated relationships between NF-κB members and their overlapping function. However, c-Rel nuclear expression correlated with significantly poorer survival in p63+ and BCL-2- activated B-cell-like-DLBCL, and in DLBCL patients with TP53 mutations. Multivariate analysis indicated that after adjusting clinical parameters, c-Rel positivity was a significantly adverse prognostic factor in DLBCL patients with wild type TP53. Gene expression profiling suggested dysregulations of cell cycle, metabolism, adhesion, and migration associated with c-Rel activation. In contrast, REL amplification did not correlate with c-Rel nuclear expression and patient survival, likely due to co-amplification of genes that negatively regulate NF-κB activation. These insights into the expression, prognostic impact, regulation and function of c-Rel as well as its crosstalk with the p53 pathway underscore the importance of c-Rel and have significant therapeutic implications.

Original languageEnglish (US)
Pages (from-to)23157-23180
Number of pages24
JournalOncotarget
Volume6
Issue number27
DOIs
StatePublished - Jan 1 2015

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Keywords

  • DLBCL
  • Gene expression profiling
  • NF-κB
  • P53
  • c-Rel

ASJC Scopus subject areas

  • Oncology

Cite this

Li, L., Xu-Monette, Z. Y., Ok, C. Y., Tzankov, A., Manyam, G. C., Sun, R., Visco, C., Zhang, M., 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., ... Young, K. H. (2015). Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma. Oncotarget, 6(27), 23157-23180. https://doi.org/10.18632/oncotarget.4319