ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype
ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype
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DOI：
10.1182/blood-2008-08-173914
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发表时间：
2009-04-09
期刊：
影响因子：
20.3
通讯作者：
Santoni, Angela
中科院分区：
文献类型：
--
作者：
Soriani, Alessandra;Zingoni, Alessandra;Santoni, Angela
有大量证据支持自然杀伤 (NK) 细胞在控制多发性骨髓瘤 (MM) 进展中的作用，多发性骨髓瘤 (MM) 是一种以骨髓 (BM) 中异常浆细胞增殖为特征的恶性肿瘤。最近已显示 DNA 损伤反应的诱导能够增强 NKG2D 配体 (NKG2DL) 的表达，但对 DNAM-1 配体 (DNAM-1L) 的调节尚不清楚。在这项研究中，我们发现，用多柔比星、美法仑和硼替佐米等多柔比星、美法仑和硼替佐米等常用的低剂量治疗药物治疗骨髓瘤细胞后，DNAM-1 和 NKG2D 配体上调。因此，MM细胞的治疗药物治疗会增加NK细胞脱颗粒，NKG2D和DNAM-1受体是主要的触发分子。使用来自 MM 患者的离体原代浆细胞也获得了类似的数据。用 ATM（毛细血管扩张共济失调突变）和 ATR（ATM 和 RAD3 相关）药物抑制剂咖啡因和 KU-55933 治疗后，药物诱导的 DNAM-1 和 NKG2D 配体表达被消除，并且优先与停滞在细胞周期 G2 期的衰老细胞相关。总而言之，我们的研究结果确定了一个可以触发不同 NK 细胞激活配体上调的共同途径，并表明 NK 细胞代表了对经历应激诱导衰老程序的细胞的免疫监视机制。 （血。2009；113：3503-3511）
There is much evidence to support a role for natural killer (NK) cells in controlling the progression of multiple myeloma (MM), a malignancy characterized by an abnormal plasma cell proliferation in the bone marrow (BM). Induction of DNA damage response has been recently shown capable of enhancing NKG2D ligand (NKG2DL) expression, but nothing is known about DNAM-1 ligand (DNAM-1L) regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bortezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, the NKG2D and DNAM-1 receptors being the major triggering molecules. Similar data were also obtained using ex vivo primary plasma cells derived from MM patients. Drug-induced DNAM-1 and NKG2D ligand expression was abolished after treatment with the ATM (ataxia telangiectasia mutated) and ATR (ATM-and RAD3-related) pharmacologic inhibitors caffeine and KU-55933, and was preferentially associated with senescent cells arrested in the G2 phase of the cell cycle. Altogether, our findings have identified a common pathway that can trigger the up-regulation of different NK cell-activating ligands and suggest that NK cells represent an immunosurveillance mechanism toward cells undergoing stress-induced senescent programs. (Blood. 2009; 113: 3503-3511)