Division of Hematology and Oncology, Department of Medicine, University of Virginia Cancer Center, University of Virginia, Charlottesville, VA; and.
Penn State College of Medicine, Hershey, PA.
Blood. 2018 Jun 21;131(25):2803-2815. doi: 10.1182/blood-2017-09-808816. Epub 2018 Apr 26.
Large granular lymphocyte (LGL) leukemia results from clonal expansion of CD3 cytotoxic T lymphocytes or CD3 natural killer (NK) cells. Chronic antigen stimulation is postulated to promote long-term survival of LGL leukemia cells through constitutive activation of multiple survival pathways, resulting in global dysregulation of apoptosis and resistance to activation-induced cell death. We reported previously that nuclear factor κB (NF-κB) is a central regulator of the survival network for leukemic LGL. However, the mechanisms that trigger constitutive activation of NF-κB in LGL leukemia remain undefined. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in tumor cells but can also activate NF-κB through interaction with TRAIL receptors 1, 2, and 4 (also known as DR4, DR5, and DcR2, respectively). The role of TRAIL has not been studied in LGL leukemia. In this study, we hypothesized that TRAIL interaction with DcR2 contributes to NF-κB activation in LGL leukemia. We observed upregulated TRAIL messenger RNA and protein expression in LGL leukemia cells with elevated levels of soluble TRAIL protein in LGL leukemia patient sera. We also found that DcR2 is the predominant TRAIL receptor in LGL leukemia cells. We demonstrated that TRAIL-induced activation of DcR2 led to increased NF-κB activation in leukemic LGL. Conversely, interruption of TRAIL-DcR2 signaling led to decreased NF-κB activation. Finally, a potential therapeutic application of proteasome inhibitors (bortezomib and ixazomib), which are known to inhibit NF-κB, was identified through their ability to decrease proliferation and increase apoptosis in LGL leukemia cell lines and primary patient cells.
大颗粒淋巴细胞（LGL）白血病是由 CD3 细胞毒性 T 淋巴细胞或 CD3 自然杀伤（NK）细胞克隆性扩增引起的。据推测，慢性抗原刺激通过多条存活途径的组成性激活，促进 LGL 白血病细胞的长期存活，导致细胞凋亡和对激活诱导的细胞死亡的抵抗的全局失调。我们之前报道过核因子 κB（NF-κB）是白血病 LGL 存活网络的中央调节剂。然而，导致 LGL 白血病中 NF-κB 组成性激活的机制仍不清楚。肿瘤坏死因子相关凋亡诱导配体（TRAIL）已知可诱导肿瘤细胞凋亡，但也可通过与 TRAIL 受体 1、2 和 4（分别称为 DR4、DR5 和 DcR2）相互作用激活 NF-κB。TRAIL 在 LGL 白血病中的作用尚未得到研究。在这项研究中，我们假设 TRAIL 与 DcR2 的相互作用有助于 LGL 白血病中 NF-κB 的激活。我们观察到 LGL 白血病细胞中 TRAIL 信使 RNA 和蛋白表达上调，LGL 白血病患者血清中可溶性 TRAIL 蛋白水平升高。我们还发现 DcR2 是 LGL 白血病细胞中主要的 TRAIL 受体。我们证明 TRAIL 诱导的 DcR2 激活导致白血病性 LGL 中 NF-κB 的激活增加。相反，阻断 TRAIL-DcR2 信号导致 NF-κB 激活减少。最后，通过其在 LGL 白血病细胞系和原代患者细胞中减少增殖和增加凋亡的能力，确定了蛋白酶体抑制剂（硼替佐米和伊沙佐米）的潜在治疗应用，蛋白酶体抑制剂已知可抑制 NF-κB。
