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.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous aggressive non-Hodgkin lymphoma that can be classified into germinal center B-like (GCB) or activated B-cell-like (ABC) DLBCL
We aimed to evaluate the clinical significance of c-Rel nuclear expression and REL amplification in DLBCL patients, to gain insight into the underlying biology, c-Rel function, activation mechanisms, and relationship with other NF-κB subunits
Decrease of Myc may result from MYC repression by FOXP3 [42] and posttranslational regulation of Myc stability by the ubiquitin-proteasome system. This was suggested by the upregulation of FOXP3 (Fig. 3F-3G) in c-Rel+ DLBCL which was opposite to the decrease of Myc in c-Rel+ DLBCL (≥5% and 30% cutoff respectively) (Fig. 3B3C), and upregulation of FBXW7 (Fig. 3H), PIN1 (P < 0.0001), and PPP2R2A (P = 0.043) in c-Rel+ GCB-DLBCL
Summary
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous aggressive non-Hodgkin lymphoma that can be classified into germinal center B-like (GCB) or activated B-cell-like (ABC) DLBCL. C-Rel encoded by the REL gene is a unique NF-κB member, predominantly expressed in lymphoid and myeloid tissues, likely contributed by the unique regulators for c-Rel activation. WT-p53 negatively regulates NF-κB activation and function [25, 26], whereas MUT-p53 induces p52/NFKB2 gene expression [27]. In head and neck squamous cell carcinoma with MUT-p53, c-Rel overexpression activated by TNF-α modulates ΔNp63α/ Tap interactions and their function, promoting proliferation and cell survival [30]. We aimed to evaluate the clinical significance of c-Rel nuclear expression and REL amplification in DLBCL patients, to gain insight into the underlying biology, c-Rel function, activation mechanisms, and relationship with other NF-κB subunits
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