Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

Chi Young Ok, Zijun Y. Xu-Monette, Ling Li, Ganiraju C. Manyam, Santiago Montes-Moreno, Alexandar Tzankov, Carlo Visco, Karen Dybkær, Mark J. Routbort, Li Zhang, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W.L. Choi, J. Han Van Krieken, Jooryung Huh, Maurilio PonzoniAndrés J.M. Ferreri, Ben M. Parsons, Huilan Rao, Michael B. Møller, Jane N. Winter, Miguel A. Piris, Sa A. Wang, L. Jeffrey Medeiros, Ken H. Young*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Nuclear factor-κB (NF-κB) is a transcription factor with a well-described oncogenic role. Study for each of five NF-κB pathway subunits was only reported on small cohorts in diffuse large B-cell lymphoma (DLBCL). In this large cohort (n=533) of patients with de novo DLBCL, we evaluated the protein expression frequency, gene expression signature, and clinical implication for each of these five NF-κB subunits. Expression of p50, p52, p65, RELB, and c-Rel was 34%, 12%, 20%, 14%, and 23%, whereas p50/p65, p50/c-Rel, and p52/RELB expression was 11%, 11%, and 3%, respectively. NF-κB subunits were expressed in both germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, but p50 and p50/c-Rel were associated with ABC-DLBCL. p52, RELB, and p52/RELB expressions were associated with CD30 expression. p52 expression was negatively associated with BCL2 (B-cell lymphoma 2) expression and BCL2 rearrangement. Although p52 expression was associated with better progression-free survival (PFS) (P=0.0170), singular expression of the remaining NF-κB subunits alone did not show significant prognostic impact in the overall DLBCL cohort. Expression of p52/RELB was associated with better overall survival (OS) and PFS (P=0.0307 and P=0.0247). When cases were stratified into GCB- and ABC-DLBCL, p52 or p52/RELB dimer expression status was associated with better OS and PFS (P=0.0134 and P=0.0124) only within the GCB subtype. However, multivariate analysis did not show p52 expression to be an independent prognostic factor. Beneficial effect of p52 in GCB-DLBC appears to be its positive correlation with CD30 and negative correlation with BCL2 expression. Gene expression profiling (GEP) showed that p52 + GCB-DLBCL was distinct from p52 - GCB-DLBCL. Collectively, our data suggest that DLBCL patients with p52 expression might not benefit from therapy targeting the NF-κB pathway.

Original languageEnglish (US)
Pages (from-to)1202-1213
Number of pages12
JournalModern Pathology
Volume28
Issue number9
DOIs
StatePublished - Sep 3 2015

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Ok, C. Y., Xu-Monette, Z. Y., Li, L., Manyam, G. C., Montes-Moreno, S., Tzankov, A., Visco, C., Dybkær, K., Routbort, M. J., Zhang, L., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K. L., Hsi, E. D., Choi, W. W. L., Van Krieken, J. H., Huh, J., ... Young, K. H. (2015). Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions. Modern Pathology, 28(9), 1202-1213. https://doi.org/10.1038/modpathol.2015.76