Increased PRAME-specific CTL killing of acute myeloid leukemia cells by either a novel histone deacetylase inhibitor chidamide alone or combined treatment with decitabine.
Increased PRAME-specific CTL killing of acute myeloid leukemia cells by either a novel histone deacetylase inhibitor chidamide alone or combined treatment with decitabine.
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单独使用新型组蛋白脱乙酰酶抑制剂西达本胺或与地西他滨联合治疗可增加 PRAME 特异性 CTL 对急性髓系白血病细胞的杀伤作用
DOI：
10.1371/journal.pone.0070522
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yu L
中科院分区：
文献类型：
--
作者：
Yao Y;Zhou J;Wang L;Gao X;Ning Q;Jiang M;Wang J;Wang L;Yu L
作为最知名的癌症睾丸抗原之一，PRAME仅在生殖系组织如睾丸以及各种实体和血液恶性细胞（包括急性髓性白血病）中过表达。因此，PRAME已被认为是主动和过继性抗白血病免疫治疗的有希望的靶点。然而，在大多数表达PRAME的急性髓性白血病患者中，PRAME抗原特异性CD 8 + CTL应答要么检测不到，要么太弱而不能发挥免疫监视，这可能是由于白血病细胞的PRAME抗原表达和PRAME特异性抗原呈递不足。在这项研究中，我们观察到显着增加PRAME mRNA表达的人急性髓性白血病细胞系和原代急性髓性白血病细胞治疗后，一种新的亚型选择性组蛋白去乙酰化酶抑制剂chidamide在体外。PRAME表达在急性髓系白血病细胞系中进一步增强后，与西达米特和DNA去甲基化剂地西他滨联合治疗。用西达米特和/或地西他滨预处理HLA-A0201+急性髓性白血病细胞系THP-1增加了对识别由HLA-A0201呈递的PRAME 100 -108或PRAME 300 -309肽的纯化CTL的敏感性。西他酰胺诱导的CD 86的表观遗传上调也有助于增加PRAME抗原特异性CTL的细胞毒性。因此，我们的数据提供了一条新的证据，即通过亚型选择性HDAC抑制剂或与低甲基化剂组合，癌症睾丸抗原的表观遗传上调增加了CTL细胞毒性，并可能代表未来设计特异性靶向表达PRAME的急性髓性白血病治疗策略的新机会。
As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME-expressing acute myeloid leukemia, PRAME antigen-specific CD8+ CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201+ acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME100–108 or PRAME300–309 peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME-expressing acute myeloid leukemia.
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CS055 (Chidamide/HBI-8000) 是一种新型组蛋白脱乙酰酶抑制剂，可诱导人白血病细胞 G1 期阻滞、ROS 依赖性细胞凋亡和分化
影响因子：
4.1
作者：
Gong, Ke;Xie, Jia;Li, Wenhua
通讯作者：
Li, Wenhua
影响因子：
20.3
作者：
Goodyear, Oliver;Agathanggelou, Angelo;Craddock, Charles
通讯作者：
Craddock, Charles
影响因子：
12.8
作者：
Atanackovic, Djordje;Luetkens, Tim;Kroeger, Nicolaus
通讯作者：
Kroeger, Nicolaus
影响因子：
4.4
作者：
Northrop, John K.;Wells, Andrew D.;Shen, Hao
通讯作者：
Shen, Hao
DOI：
10.1016/j.bbrc.2010.01.011
发表时间：
2010-02-05
影响因子：
3.1
作者：
Liu, Lin;Chen, Baoan;Zhao, Hong
通讯作者：
Zhao, Hong