c-Rel Is the Pivotal NF-κB Subunit in Germinal Center Diffuse Large B-Cell Lymphoma: A LYSA Study

Relationships between c-Rel and GCB-DLBCLs remain unclear. We found that strong c-Rel DNA-binding activity was mostly found in GCBs on two independent series of 48 DLBCLs and 66 DLBCLs, the latter issued from the GHEDI series. c-Rel DNA-binding activity was associated with increased REL mRNA expression. Extending the study to the whole GHEDI and Lenz DLBCL published series of 202 and 233 cases, it was found that the c-Rel gene expression profile (GEP) overlapped partially (12%) but only with the GCB GEP and not with the GEP of ABC-DLBCLs. Cases with both overexpression of REL mRNA and c-Rel GEP were defined as those having a c-Rel signature. These cases were GCBs in 88 and 83% of the GHEDI or Lenz's DLBCL series respectively. The c-Rel signature was also associated with various recurrent GCB-DLBCL genetic events, including REL gains, BCL2 translocation, MEF2B, EZH2, CREBBP, and TNFRSF14 mutations and with the EZB GCB genetic subtype. By CGH array, the c-Rel signature was specifically correlated with 2p15-16.1 amplification that includes XPO1, BCL11A, and USP34 and with the 22q11.22 deletion that covers IGLL5 and PRAME. The total number of gene copy number aberrations, so-called genomic imbalance complexity, was decreased in cases with the c-Rel signature. These cases exhibited a better overall survival. Functionally, overexpression of c-Rel induced its constitutive nuclear localization and protected cells against apoptosis while its repression tended to increase cell death. These results show that, clinically and biologically, c-Rel is the pivotal NF-κB subunit in the GCB-DLBCL subgroup. Functionally, c-Rel overexpression could directly promote DLBCL tumorigenesis without need for further activation signals.