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

Research output: Contribution to journalArticle

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
Pages (from-to)23157-23180
Number of pages24
JournalOncotarget
Volume6
Issue number27
DOIs
Publication statusPublished - 2015

Keywords

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

ASJC Scopus subject areas

  • Oncology

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  • 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