BIRC3 Expression Predicts CLL Progression and Defines Treatment Sensitivity via Enhanced NF-κB Nuclear Translocation
BIRC3 Expression Predicts CLL Progression and Defines Treatment Sensitivity via Enhanced NF-κB Nuclear Translocation
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DOI：
10.1158/1078-0432.ccr-18-1548
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发表时间：
2019-03-15
影响因子：
11.5
通讯作者：
Egle, Alexander
中科院分区：
文献类型：
--
作者：
Asslaber, Daniela;Wacht, Nathalie;Egle, Alexander
目的：慢性淋巴细胞白血病（CLL）的病理生理学特征是肿瘤细胞与微环境的复杂串扰。在这方面，NF-κ B信号传导被认为是重要的信号传导轴，多种关键分子在CLL患者中异常表达或发生遗传改变。BIRC 3（cIAP 2）是其中一种分子，它是非经典NF-κ B信号传导的中心调节因子，在微环境信号不存在时充当通路制动器。然而，BIRC 3表达对CLL进展和潜在治疗意义的贡献是unknown.Experimental Design：我们分析了BIRC 3 mRNA表达在与临床数据集相关的原发性CLL样品中的作用，并使用离体测定来研究NF-κ B B信号传导水平和下游靶基因调控的功能后果。对于证明的原则experiments，我们使用转基因细胞line.Results：我们证明，CLL患者与低BIRC 3表达经历了更快的疾病进展，这与典型的NF-κ B B靶基因的增强激活相一致，证明了增加的p65/Rel-B核易位率。作为增强的典型NF-κ B靶基因激活的结果，抗凋亡和促凋亡Bcl-2家族成员在BIRC 3（低）原代CLL细胞中上调，这与体外对维奈托克治疗的更高敏感性相关。在这里，我们显示了BIRC 3表达在没有BIRC 3突变的CLL疾病进展中的影响，并显示了改变的典型NF-κ B表达。具有治疗意义κ B靶基因活化。
Purpose: Chronic lymphocytic leukemia (CLL) pathophysiology is characterized by a complex crosstalk of tumor cells with the microenvironment. In this regard, NF-kappa B signaling is considered as important signaling axis, with a variety of key molecules aberrantly expressed or genetically altered in patients with CLL. One of these molecules is BIRC3 (cIAP2), a central regulator of noncanonical NF-kappa B signaling that serves as pathway brake in the absence of microenvironmental signals. However, the contribution of BIRC3 expression to CLL progression and potential therapeutic implications is unknown.Experimental Design: We analyzed the role of BIRC3 mRNA expression in primary CLL samples in correlation to clinical datasets and used ex vivo assays to investigate functional consequences on the level of NF-kappa B signaling and downstream target gene regulation. For proof-of-principle experiments, we used genetically modified cell lines.Results: We demonstrate that patients with CLL with low BIRC3 expression experience a more rapid disease progression, which coincides with an enhanced activation of canonical NF-kappa B target genes evidenced by an increased p65/Rel-B nuclear translocation ratio. As a consequence of enhanced canonical NF-kappa B target gene activation, both anti-and proapoptotic Bcl-2 family members were upregulated in BIRC3(low) primary CLL cells, which was associated with higher sensitivity to venetoclax treatment in vitro.Conclusions: Here we show the impact of BIRC3 expression in CLL disease progression in the absence of BIRC3 mutations and show altered canonical NF-kappa B target gene activation with therapeutic implications.