Hydroxyurea upregulates NKG2D ligand expression in myeloid leukemia cells synergistically with valproic acid and potentially enhances susceptibility of leukemic cells to natural killer cell-mediated cytolysis
Hydroxyurea upregulates NKG2D ligand expression in myeloid leukemia cells synergistically with valproic acid and potentially enhances susceptibility of leukemic cells to natural killer cell-mediated cytolysis
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DOI：
10.1111/j.1349-7006.2009.01439.x
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发表时间：
2010-03-01
期刊：
影响因子：
5.7
通讯作者：
Nakao, Shinji
中科院分区：
文献类型：
--
作者：
Lu, Xuzhang;Ohata, Kinya;Nakao, Shinji
丙戊酸（VPA）是一种组蛋白脱乙酰酶抑制剂，可上调某些单核细胞和淋巴白血病细胞上的NKG 2D配体（NKG 2DL）。然而，其对髓系白血病细胞的作用和可以增强VPA作用的协同剂仍然未知。在检查的各种骨髓细胞系中，慢性髓性白血病细胞系OUN-1显示出对VPA应答的云母/B和ULBP 2最显著的上调。NKG 2DL的上调只在没有凋亡的白血病细胞中观察到，并且通过用咖啡因（ATM/ATR的抑制剂）预处理细胞来消除该效应。筛选了几种ATM/ATR激活剂对NKG 2DL表达的影响，但只有羟基脲（HU）有效上调了细胞系上的云母/B和ULPB 2表达。VPA和HU协同上调OUN-1细胞以及一些急性髓性白血病患者的原代白血病细胞上的NKG 2DL。VPA和/或HU上调NKG 2DL与各NKG 2DL基因转录增加相关。VPA + HU处理的OUN-1细胞比未处理的细胞更容易被自然杀伤（NK）细胞杀死，NK细胞的细胞毒性增强可通过抗NKG 2D单克隆抗体处理NK细胞而阻断。相同浓度的VPA和HU不影响NK细胞对OUN-1细胞的杀伤活性。这些数据表明，VPA和HU可能通过增加髓系白血病细胞对NK细胞的敏感性来增强NK细胞介导的抗白血病效应。（Cancer Sci 2010; 101：609-615）
Valproic acid (VPA), a histone deacetylase inhibitor, upregulates NKG2D ligands (NKG2DLs) on some monocytic and lymphoid leukemic cells. However, its effect on myeloid leukemia cells and synergistic agents that can augment the effect of VPA remains unknown. Of the various myeloid cell lines examined, OUN-1, a chronic myelogenous leukemia cell line, showed the most prominent upregulation of MICA/B and ULBP2 in response to VPA. The NKG2DL upregulation was observed only in leukemic cells without apoptosis and the effect was abrogated by pretreatment of cells with caffeine, an inhibitor of ATM/ATR. Several activators of ATM/ATR were screened for their effect on NKG2DL expression, but only hydroxyurea (HU) efficiently upregulated both MICA/B and ULPB2 expression on the cell line. VPA and HU synergistically upregulated the NKG2DLs on OUN-1 cells as well as primary leukemic cells from some patients with acute myeloid leukemia. The upregulation of NKG2DLs by VPA and/or HU was associated with increased transcription of each NKG2DL gene. OUN-1 cells treated with VPA + HU were more susceptible to killing by natural killer (NK) cells than untreated cells and the enhanced cytotoxicity of NK cells was blocked by the treatment of NK cells with anti-NKG2D monoclonal antibodies. The same concentrations of VPA and HU did not affect the cytotoxicity of NK cells against OUN-1 cells. These data suggest that VPA and HU might enhance the NK cell-mediated antileukemia effect by increasing the susceptibility of myeloid leukemic cells to NK cells. (Cancer Sci 2010; 101: 609-615)