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. 2015 Sep 15;6(27):23157-80. doi: 10.18632/oncotarget.4319.

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: DLBCL; NF-kB; c-Rel; gene expression profiling; p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cohort Studies
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Male
  • Middle Aged
  • Mutation
  • NF-kappa B / metabolism
  • Nuclear Proteins / metabolism*
  • Prognosis
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins c-rel
  • Signal Transduction / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • DNA-Binding Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-rel
  • REL protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53