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 Journal Article
| Authors: | 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.; Ponzoni, M.; Ferreri, A. J. M.; Møller, M. B.; Wang, J.; Parsons, B. M.; Winter, J. N.; Piris, M. A.; Pham, L. V.; Jeffrey Medeiros, L.; Young, K. H. |
| Article Title: | 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 |
| 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. |
| Keywords: | protein kinase b; adult; cancer survival; controlled study; human tissue; protein expression; gene mutation; human cell; major clinical study; protein function; transcription factor foxp3; cell cycle; protein bcl 2; gene amplification; gene expression profiling; protein protein interaction; cohort analysis; immunoglobulin enhancer binding protein; wild type; protein p53; tumor suppressor gene; enzyme phosphorylation; myc protein; cell migration; protein p63; upregulation; cell nucleus; large cell lymphoma; cancer classification; cell adhesion; transcription factor fkhrl1; p53; metabolic regulation; dlbcl; nf-κb; transcription factor rel; c-rel; cancer prognosis; human; male; female; article; rel gene; foxp3 gene; foxo3 gene; germinal center b like diffuse large b cell lymphoma; meg3 gene |
| Journal Title: | Oncotarget |
| Volume: | 6 |
| Issue: | 27 |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Date Published: | 2015-09-15 |
| Start Page: | 23157 |
| End Page: | 23180 |
| Language: | English |
| DOI: | 10.18632/oncotarget.4319 |
| PROVIDER: | scopus |
| PUBMED: | 26324762 |
| PMCID: | PMC4695110 |
| DOI/URL: | |
| Notes: | Export Date: 2 November 2015 -- Source: Scopus |
