Li Ling, Xu-Monette Zijun Y, Ok Chi Young, Tzankov Alexandar, Manyam Ganiraju C, Sun Ruifang, Visco Carlo, Zhang Mingzhi, Montes-Moreno Santiago, Dybkaer Karen, Chiu April, Orazi Attilio, Zu Youli, Bhagat Govind, Richards Kristy L, Hsi Eric D, Choi William W L, van Krieken J Han, Huh Jooryung, Ponzoni Maurilio, Ferreri Andrés J M, Møller Michael B, Wang Jinfen, Parsons Ben M, Winter Jane N, Piris Miguel A, Pham Lan V, Medeiros L Jeffrey, Young Ken H
Zhengzhou University, The First Affiliated University Hospital, Zhengzhou, China.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Oncotarget. 2015 Sep 15;6(27):23157-80. doi: 10.18632/oncotarget.4319.
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.
失调的核因子-κB（NF-κB）信号传导对淋巴瘤发生至关重要。c-Rel/NF-κB激活在弥漫性大B细胞淋巴瘤（DLBCL）中的调控、功能及临床相关性尚未得到充分研究。在本研究中，我们分析了460例初发性DLBCL患者中c-Rel核表达作为c-Rel激活替代指标的预后意义及基因表达特征。在137例（26.3%）DLBCL患者中观察到核c-Rel表达，其常与结外起源相关，在总人群或生发中心B细胞样DLBCL队列中未显示出显著的预后影响，这可能是由于pAKT和Myc水平降低、FOXP3、FOXO3、MEG3及其他肿瘤抑制因子的上调与c-Rel核表达同时出现，以及NF-κB成员之间复杂的关系及其重叠功能所致。然而，在p63+和BCL-2激活的B细胞样DLBCL以及TP53突变的DLBCL患者中，c-Rel核表达与显著较差的生存率相关。多变量分析表明，在调整临床参数后，c-Rel阳性是野生型TP53的DLBCL患者的显著不良预后因素。基因表达谱分析提示与c-Rel激活相关的细胞周期、代谢、黏附和迁移失调。相比之下，REL扩增与c-Rel核表达及患者生存率无关，这可能是由于负调控NF-κB激活的基因共扩增所致。这些关于c-Rel的表达、预后影响、调控和功能及其与p53途径相互作用的见解强调了c-Rel的重要性，并具有重要的治疗意义。
