Investigation of the molecular mechanisms of constitutive NF-kBactivation for the identification of therapeutic targets of adult T-cell leukemia cells

成人T细胞白血病(ATL)是由人类T细胞白血病病毒I型感染引起的T细胞肿瘤。以往的报道描述泛素编辑酶A20通过抑制caspase-8的激活来保护细胞因子或NK诱导的内皮细胞死亡。我发现在ATL细胞中可以检测到A20蛋白和mRNA的表达，这与一些体细胞突变和/或缺失A20的B细胞淋巴瘤细胞株形成了鲜明对比。有趣的是，定量RT-PCR分析显示，ATL患者外周血单个核细胞中A20mRNA的表达经常上调。A20是ATL来源的细胞和HTLV-I转化的细胞生长所必需的。RNA干扰介导的A20基因敲除诱导了凋亡启动子caspase-8的激活，同时激活了下游效应分子caspase-3/7。此外，我还发现A20与caspase-8在物理上相互作用。重要的是，A20的缺失抑制了ATL细胞的生长，并增加了Annexin V阳性的人数。这些结果表明，A20有助于ATL细胞的存活，并暗示A20是ATL治疗的治疗分子靶点。

Adult T-cell leukemia (ATL) is a T-cell neoplasm caused by Human T-cell leukemia virus type I infection. Previous reports described that the ubiquitin-editing enzyme A20 protects cytokine- or NK-induced cell death of endothelial cells via inhibiting caspase-8 activation. I found that the A20 protein and mRNA expressions were detectable in ATL cells in contrast to some of B-cell lymphoma cell lines with a somatic mutation and/or deletion of A20. Interestingly, quantitative RT-PCR analysis revealed that the A20 mRNA expression was frequently up-regulated in PBMCs derived from ATL patients. And A20 was found to be required for the growth of ATL-derived and HTLV-I-transformed cells. RNA-interference mediated knock-down of A20 induced the activation of apoptosis initiator caspase-8 concomitant with the activation of downstream effector caspase-3/7. In addition, I found that A20 physically interacts with caspase-8. Importantly, depletion of A20 suppressed the growth of ATL cells and increased the annexin V-positive population. These results suggest that A20 contributes to the survival of ATL cells and implicates A20 as a therapeutic molecular target for ATL therapy.