TY - JOUR
T1 - 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
AU - Li, Ling
AU - Xu-Monette, Zijun Y.
AU - Ok, Chi Young
AU - Tzankov, Alexandar
AU - Manyam, Ganiraju C.
AU - Sun, Ruifang
AU - Visco, Carlo
AU - Zhang, Mingzhi
AU - Montes-Moreno, Santiago
AU - Dybkaer, Karen
AU - Chiu, April
AU - Orazi, Attilio
AU - Zu, Youli
AU - Bhagat, Govind
AU - Richards, Kristy L.
AU - Hsi, Eric D.
AU - Choi, William W.L.
AU - van Krieken, J. Han
AU - Huh, Jooryung
AU - Ponzoni, Maurilio
AU - Ferreri, Andrés J.M.
AU - Møller, Michael B.
AU - Wang, Jinfen
AU - Parsons, Ben M.
AU - Winter, Jane N.
AU - Piris, Miguel A.
AU - Pham, Lan V.
AU - Jeffrey Medeiros, L.
AU - Young, Ken H.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - DLBCL
KW - Gene expression profiling
KW - NF-κB
KW - P53
KW - c-Rel
UR - http://www.scopus.com/inward/record.url?scp=84942999810&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84942999810&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.4319
DO - 10.18632/oncotarget.4319
M3 - Article
C2 - 26324762
AN - SCOPUS:84942999810
SN - 1949-2553
VL - 6
SP - 23157
EP - 23180
JO - Oncotarget
JF - Oncotarget
IS - 27
ER -