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首页> 外文期刊>Clinical epigenetics. >Epigenetic therapy of acute myeloid leukemia using 5-aza-2'-deoxycytidine (decitabine) in combination with inhibitors of histone methylation and deacetylation
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Epigenetic therapy of acute myeloid leukemia using 5-aza-2'-deoxycytidine (decitabine) in combination with inhibitors of histone methylation and deacetylation

机译：5-氮杂-2'-脱氧胞苷（地西他滨）联合组蛋白甲基化和脱乙酰基抑制剂联合应用的表观遗传学治疗急性髓细胞白血病

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BackgroundThe silencing of tumor suppressor genes (TSGs) by aberrant DNA methylation occurs frequently in acute myeloid leukemia (AML). This epigenetic alteration can be reversed by 5-aza-2’-deoxcytidine (decitabine, 5-AZA-CdR). Although 5-AZA-CdR can induce complete remissions in patients with AML, most patients relapse. The effectiveness of this therapy may be limited by the inability of 5-AZA-CdR to reactivate all TSGs due to their silencing by other epigenetic mechanisms such as histone methylation or chromatin compaction. EZH2, a subunit of the polycomb repressive complex 2, catalyzes the methylation of histone H3 lysine 27 (H3K27) to H3K27me3. 3-Deazaneplanocin-A (DZNep), an inhibitor of methionine metabolism, can reactivate genes silenced by H3K27me3 by its inhibition of EZH2. In a previous report, we observed that 5-AZA-CdR, in combination with DZNep, shows synergistic antineoplastic action against AML cells. Gene silencing due to chromatin compaction is attributable to the action of histone deacetylases (HDAC). This mechanism of epigenetic gene silencing can be reversed by HDAC inhibitors such as trichostatin-A (TSA). Silent TSGs that cannot be reactivated by 5-AZA-CdR or DZNep have the potential to be reactivated by TSA. This provides a rationale for the use of HDAC inhibitors in combination with 5-AZA-CdR and DZNep to treat AML. ResultsThe triple combination of 5-AZA-CdR, DZNep, and TSA induced a remarkable synergistic antineoplastic effect against human AML cells as demonstrated by an in vitro colony assay. This triple combination also showed a potent synergistic activation of several key TSGs as determined by real-time PCR. The triple combination was more effective than the combination of two agents or a single agent. Microarray analysis showed that the triple combination generated remarkable changes in global gene expression. ConclusionsOur data suggest that it may be possible to design a very effective therapy for AML using agents that target the reversal of the following three epigenetic “lock” mechanisms that silence gene expression: DNA methylation, histone methylation, and histone deacetylation. This approach merits serious consideration for clinical investigation in patients with advanced AML.
机译：背景技术异常的DNA甲基化使肿瘤抑制基因（TSG）沉默在急性髓细胞性白血病（AML）中经常发生。这种表观遗传学改变可以被5-氮杂-2'-脱氧胞苷（地他滨，5-AZA-CdR）逆转。尽管5-AZA-CdR可以诱导AML患者完全缓解，但大多数患者会复发。由于5-AZA-CdR无法通过其他表观遗传机制（例如组蛋白甲基化或染色质紧实化）使其沉默，因此5-AZA-CdR无法重新激活所有TSG可能会限制该疗法的有效性。 EZH2是多梳抑制复合物2的一个亚基，催化组蛋白H3赖氨酸27（H3K27）甲基化为H3K27me3。 3-Deazaneplanocin-A（DZNep）是蛋氨酸代谢的抑制剂，可通过抑制EZH2来激活H3K27me3沉默的基因。在以前的报告中，我们观察到5-AZA-CdR与DZNep结合显示对AML细胞的协同抗肿瘤作用。由于染色质紧实而导致的基因沉默可归因于组蛋白脱乙酰基酶（HDAC）的作用。表观遗传基因沉默的这种机制可以被HDAC抑制剂（例如曲古抑菌素A（TSA））逆转。无法通过5-AZA-CdR或DZNep重新激活的静默TSG有可能被TSA重新激活。这为将HDAC抑制剂与5-AZA-CdR和DZNep联合用于治疗AML提供了理论依据。结果5-AZA-CdR，DZNep和TSA的三联组合可诱导抗人AML细胞的显着协同抗肿瘤作用，这一点已通过体外菌落试验证明。该三重组合还显示了通过实时PCR确定的几种关键TSG的有效协同激活。三联组合比两种药物或单一药物的组合更有效。微阵列分析表明，三重组合在全局基因表达中产生了显着变化。结论我们的数据表明，使用靶向以下三种沉默基因表达的表观遗传“锁定”机制的逆转剂，可以设计出一种非常有效的AML治疗方法：DNA甲基化，组蛋白甲基化和组蛋白脱乙酰化。对于晚期AML患者，此方法值得临床研究认真考虑。

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