NF-κB p50 activation associated with immune dysregulation confers poorer survival for diffuse large B-cell lymphoma patients with wild-type p53
NF-κB p50 activation associated with immune dysregulation confers poorer survival for diffuse large B-cell lymphoma patients with wild-type p53
复制标题
与免疫失调相关的 NF-kappa B p50 激活导致野生型 p53 弥漫性大 B 细胞淋巴瘤患者的生存率较差
DOI：
10.1038/modpathol.2017.5
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发表时间：
2017-06-01
期刊：
影响因子：
7.5
通讯作者：
Young, Ken H.
中科院分区：
文献类型：
--
作者：
Cai, Qingqing;Tu, Meifeng;Young, Ken H.
NF-κ B信号转导失调是淋巴瘤发生的关键，然而，NF-κ B亚基p50在弥漫性大B细胞淋巴瘤中的表达和临床相关性尚未得到评价。在这项研究中，我们分析了465例原发性弥漫性大B细胞淋巴瘤患者p50核表达作为p50激活的替代物的预后意义和基因表达特征。我们发现p50（+）核表达在34.6%的弥漫性大B细胞淋巴瘤中观察到，主要由活化B细胞样亚型组成，是活化B细胞样弥漫性大B细胞淋巴瘤患者的独立不良预后因素。它也是野生型TP 53患者的不良预后因素，与活化的B细胞样和生发中心B细胞样亚型无关，尽管p50活化与Myc、PI 3 K、磷酸化AKT和CXCR 4表达水平显著降低以及BCL 2易位频率降低相关。相反，在伴有TP 53突变的生发中心B细胞样弥漫性大B细胞淋巴瘤患者中，p50（+）核表达与显著更好的临床结局相关，并且p53、Bcl-2和Myc表达降低。基因表达谱分析揭示了通过经典或非经典NF-κ B途径可能在p50激活上游的多种信号传导途径，并表明免疫抑制，包括免疫检查点TIM-3的免疫抑制和通过白细胞免疫球蛋白样受体的免疫抑制，但不包括抗凋亡和增殖，可能是弥漫性大B细胞淋巴瘤中观察到的与p50（+）核表达相关的较差生存率的基础。总之，这些数据表明，p50作为活化B细胞样弥漫性大B细胞淋巴瘤和没有TP 53突变的患者中R-CHOP耐药的独特机制是重要的。这些结果也为p50在弥漫性大B细胞淋巴瘤中的调节和功能及其与p53通路的相互作用提供了重要的治疗意义。
Dysregulated NF-kappa B signaling is critical for lymphomagenesis, however, the expression and clinical relevance of NF-kappa B subunit p50 in diffuse large B-cell lymphoma have not been evaluated. In this study, we analyzed the prognostic significance and gene expression signatures of p50 nuclear expression as a surrogate for p50 activation in 465 patients with de novo diffuse large B-cell lymphoma. We found that p50(+) nuclear expression, observed in 34.6% of diffuse large B-cell lymphoma, predominantly composed of activated B-cell-like subtype, was an independent adverse prognostic factor in patients with activated B-cell-like diffuse large B-cell lymphoma. It was also an adverse prognostic factor in patients with wild-type TP53 independent of the activated B-cell-like and germinal center B-cell-like subtypes, even though p50 activation correlated with significantly lower levels of Myc, PI3K, phospho-AKT, and CXCR4 expression and less frequent BCL2 translocations. In contrast, in germinal center B-cell-like diffuse large B-cell lymphoma patients with TP53 mutations, p50(+) nuclear expression correlated with significantly better clinical outcomes, and decreased p53, Bcl-2, and Myc expression. Gene expression profiling revealed multiple signaling pathways potentially upstream the p50 activation through either canonical or noncanonical NF-kappa B pathways, and suggested that immune suppression, including that by the immune checkpoint TIM-3 and that through leukocyte immunoglobulin-like receptors, but not antiapoptosis and proliferation, may underlie the observed poorer survival rates associated with p50(+) nuclear expression in diffuse large B-cell lymphoma. In conclusion, these data show that p50 is important as a unique mechanism of R-CHOP-resistance in activated B-cell-like diffuse large B-cell lymphoma and in patients without TP53 mutations. The results also provide insights into the regulation and function of p50 in diffuse large B-cell lymphoma and its cross talk with the p53 pathway with important therapeutic implications.