Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas.
Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas.
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组蛋白脱乙酰基酶抑制剂下调CCR4的表达，并降低CCR4阳性成熟T细胞淋巴瘤中的大木珠单抗功效。
DOI：
10.3324/haematol.2017.177279
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发表时间：
2018-01
期刊：
影响因子：
10.1
通讯作者：
Tagawa H
中科院分区：
文献类型：
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作者：
Kitadate A;Ikeda S;Abe F;Takahashi N;Shimizu N;Matsue K;Tagawa H
组蛋白去乙酰酶抑制剂是治疗各种T细胞淋巴瘤的有前途的药物，包括皮肤T细胞淋巴瘤、外周T细胞淋巴瘤和成人T细胞淋巴瘤/白血病。CCR4是一种重要的治疗靶分子，因为抗CCR4的单抗MoGamulizumab对各种T细胞淋巴瘤显示出良好的疗效。在这项研究中，我们检测了莫古珠单抗和组蛋白去乙酰酶抑制剂对各种T细胞淋巴瘤的体外协同作用。首先，我们检测了不同T细胞淋巴瘤细胞系中CCR4mRNA和表面CCR4的表达，发现在泛组蛋白去乙酰化酶抑制剂Vorinostat处理后，CCR4的表达下调。接下来，我们使用异构体特异性的组蛋白脱乙酰酶抑制剂和短干扰RNA来确定参与CCR4调控的组蛋白脱乙酰酶异构体，结果表明I类选择性组蛋白脱乙酰酶抑制剂罗米地辛对CCR4的抑制作用最强。此外，在I类组蛋白脱乙酰酶中，组蛋白脱乙酰酶2基因敲除导致淋巴瘤细胞中CCR4的表达减少，表明CCR4的表达主要受组蛋白脱乙酰酶2的调控。当我们检测来自相同患者的原发皮肤T细胞淋巴瘤患者治疗前后CCR4的表达时，我们发现治疗后CCR4的表达显著降低。最后，当我们用不同的淋巴瘤细胞对莫伽慕珠单抗进行抗体依赖的细胞介导的细胞毒试验时，我们发现莫伽慕珠单抗的疗效被伏立诺坦预处理后显著降低。综上所述，我们的研究结果表明，在莫伽珠单抗治疗之前主要使用组蛋白去乙酰化酶抑制剂可能不适合获得协同效应。此外，这些结果对各种CCR4阳性T细胞淋巴瘤的最佳治疗顺序具有潜在的指导意义。
Histone deacetylase inhibitors are promising agents for various T-cell lymphomas, including cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia. CCR4 is an important therapeutic target molecule because mogamulizumab, an anti-CCR4 antibody, has shown promising efficacy against various T-cell lymphomas. In this study, we examined the in vitro synergistic effects of mogamulizumab and histone deacetylase inhibitors against various T-cell lymphomas. First, we examined the expression of CCR4 mRNA and surface CCR4 in various T-cell lymphoma cell lines and found that it was downregulated upon treatment with vorinostat, a pan-histone deacetylase inhibitor. Next, we used isoform-specific histone deacetylase inhibitors and short-interfering RNA to determine the histone deacetylase isoform involved in the regulation of CCR4, and demonstrated that romidepsin, a class I selective histone deacetylase inhibitor, reduced CCR4 most efficiently. Moreover, among class I histone deacetylases, histone deacetylase 2 knockdown led to a reduction of CCR4 in lymphoma cells, suggesting that CCR4 expression is mainly regulated by histone deacetylase 2. When we examined the CCR4 expression in skin samples from primary cutaneous T-cell lymphoma, obtained from the same patients before and after vorinostat treatment, we found that CCR4 expression was greatly reduced after treatment. Finally, when we conducted an antibody-dependent cell-mediated cytotoxicity assay with mogamulizumab by using various lymphoma cells, we found that the efficacy of mogamulizumab was significantly reduced by pretreatment with vorinostat. Altogether, our results suggest that the primary use of histone deacetylase inhibitors before treatment with mogamulizumab might not be suitable to obtain synergistic effects. Moreover, these results have potential implications for optimal therapeutic sequences in various CCR4-positive T-cell lymphomas.
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影响因子：
11.5
作者：
Ni, Xiao;Jorgensen, Jeffrey L.;Duvic, Madeleine A.
通讯作者：
Duvic, Madeleine A.
影响因子：
2.9
作者：
O'Leary, Hilary M;Savage, Kerry J
通讯作者：
Savage, Kerry J
影响因子：
5.7
作者：
Hasanali, Zainul S.;Epner, Elliot M.;Sample, Clare E.
通讯作者：
Sample, Clare E.
影响因子：
45.3
作者：
O'Connor, Owen A.;Horwitz, Steven;Shustov, Andrei
通讯作者：
Shustov, Andrei
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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