Dysregulation of TNFα-induced necroptotic signaling in chronic lymphocytic leukemia: suppression of CYLD gene by LEF1
Dysregulation of TNFα-induced necroptotic signaling in chronic lymphocytic leukemia: suppression of CYLD gene by LEF1
复制标题
慢性淋巴细胞白血病中 TNFα 诱导的坏死性凋亡信号失调：LEF1 抑制 CYLD 基因
DOI：
10.1038/leu.2011.357
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发表时间：
2012-06-01
期刊：
影响因子：
11.4
通讯作者：
Li, J.
中科院分区：
文献类型：
--
作者：
Liu, P.;Xu, B.;Li, J.
细胞死亡程序受损是慢性淋巴细胞性白血病（CLL）的标志之一，并导致其恶性单克隆B细胞的积累以及化疗抗性。细胞可以通过细胞凋亡或坏死途径死亡。最近的研究表明，在细胞凋亡缺陷的情况下，例如大多数类型的癌症，普遍存在程序性坏死过程，称为坏死性凋亡。然而，这种替代细胞死亡途径的详细分子机制仍然没有完全理解。在这里，我们证明了CLL细胞在TNFα与泛半胱天冬酶抑制剂苄氧羰基-Val-Ala-Asp-氟甲基酮（zVAD）联合刺激后未能发生坏死性凋亡。坏死性凋亡机制的两个核心成分RIP 3和去泛素化圆柱瘤病（CYLD）在CLL中显著下调。此外，我们确定了淋巴增强子结合因子1（LEF 1），Wnt/β-catenin途径的下游效应子，作为CLL中CYLD的转录抑制因子。敲低LEF 1使CLL细胞对TNFα/zVAD诱导的坏死性凋亡敏感。本研究首次证明CLL细胞不仅在凋亡程序上存在缺陷，而且在坏死性凋亡信号传导上也存在缺陷。靶向坏死性凋亡机制的关键调节因子，如LEF 1，以恢复这一途径可能代表了CLL治疗的新方法。
Impaired cell death program has been noted as one of the hallmarks of chronic lymphocytic leukemia (CLL) and contributes to its accumulation of malignant monoclonal B cells as well as to chemotherapy resistance. A cell can die through the apoptosis or necrosis pathway. Recent investigations suggest that in apoptotic-deficient conditions, such as most types of cancer, a process of programmed necrosis, called necroptosis, prevails. However, the detailed molecular mechanisms underlying this alternative cell death pathway are still not fully understood. Here we demonstrate that CLL cells failed to undergo necroptosis upon stimulation of TNFα combined with pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD). Two core components of necroptotic machine, RIP3 and deubiquitinase cylindromatosis (CYLD), are markedly downregulated in CLL. Moreover, we identified lymphoid enhancer-binding factor 1 (LEF1), a downstream effector of the Wnt/β-catenin pathway, as a transcription repressor of CYLD in CLL. Knocking down LEF1 sensitizes CLL cells to TNFα/zVAD-induced necroptosis. The present investigation provides the first evidence that CLL cells have defects not only in apoptotic program but also in necroptotic signaling. Targeting the key regulators of necroptotic machine, such as LEF1, to restore this pathway may represent a novel approach for CLL treatment.