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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

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.
Krieken, J.H.J.M. van
Huh, J.
Ponzoni, M.
Ferreri, A.J.
Moller, M.B.
Wang, J
Parsons, B.M.
Winter, J.N.
Piris, M.A.
Pham, L.V.
Medeiros, L.J.
Young, K.H.
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.
Krieken, J.H.J.M. van
Huh, J.
Ponzoni, M.
Ferreri, A.J.
Moller, M.B.
Wang, J
Parsons, B.M.
Winter, J.N.
Piris, M.A.
Pham, L.V.
Medeiros, L.J.
Young, K.H.
Source :
Oncotarget; 23157; 23180; 1949-2553; 27; 6; ~Oncotarget~23157~23180~~~1949-2553~27~6~~
Publication Year :
2015

Abstract

Contains fulltext : 153743.pdf (publisher's version ) (Closed access)<br />Dysregulated NF-kappaB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-kappaB 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-kappaB 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-kappaB 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.

Details

Database :
OAIster
Journal :
Oncotarget; 23157; 23180; 1949-2553; 27; 6; ~Oncotarget~23157~23180~~~1949-2553~27~6~~
Publication Type :
Electronic Resource
Accession number :
edsoai.on1284034736
Document Type :
Electronic Resource