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.
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.
Zhengzhou University, The First Affiliated University Hospital, Zhengzhou, China.|Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ling
L
Li
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Zijun Y
ZY
Xu-Monette
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Chi Young
CY
Ok
University Hospital, Basel, Switzerland.
Alexandar
A
Tzankov
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ganiraju C
GC
Manyam
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ruifang
R
Sun
San Bortolo Hospital, Vicenza, Italy.
Carlo
C
Visco
Zhengzhou University, The First Affiliated University Hospital, Zhengzhou, China.
Mingzhi
M
Zhang
Hospital Universitario Marques de Valdecilla, Santander, Spain.
Santiago
S
Montes-Moreno
Aalborg Univwersity Hospital, Aalborg, Denmark.
Karen
K
Dybkaer
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
April
A
Chiu
Weill Medical College of Cornell University, New York, NY, USA.
Attilio
A
Orazi
The Methodist Hospital, Houston, TX, USA.
Youli
Y
Zu
Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
Govind
G
Bhagat
University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Kristy L
KL
Richards
Cleveland Clinic, Cleveland, OH, USA.
Eric D
ED
Hsi
University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China.
William W L
WW
Choi
Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
J Han
JH
van Krieken
Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea.
Jooryung
J
Huh
San Raffaele H. Scientific Institute, Milan, Italy.
Maurilio
M
Ponzoni
San Raffaele H. Scientific Institute, Milan, Italy.
Andrés J M
AJ
Ferreri
Odense University Hospital, Odense, Denmark.
Michael B
MB
Møller
Shanxi Cancer Hospital, Shanxi, China.
Jinfen
J
Wang
Gundersen Medical Foundation, La Crosse, WI, USA.
Ben M
BM
Parsons
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Jane N
JN
Winter
Hospital Universitario Marques de Valdecilla, Santander, Spain.
Miguel A
MA
Piris
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lan V
LV
Pham
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
L Jeffrey
LJ
Medeiros
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas, USA.
Ken H
KH
Young
D000368:Aged; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D020569:Proto-Oncogene Proteins c-rel; C068059:REL protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
DLBCL; NF-kB; c-Rel; gene expression profiling; p53