Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells
Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells
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DOI：
10.1038/sj.onc.1210820
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发表时间：
2008-03-13
期刊：
影响因子：
8
通讯作者：
Santini, V.
中科院分区：
文献类型：
--
作者：
Barbetti, V.;Gozzini, A.;Santini, V.
我们分析了一种新的羟酸衍生物ITF2357对AML细胞的体外作用。ITF2357有效诱导组蛋白乙酰化。0.1 μ M的ITF2357对AML1/ eto阳性的Kasumi-1细胞具有抑制增殖和诱导凋亡的作用，而AML1/ eto阴性的HL60、THP1和NB4细胞系仅对1 μ M的ITF2357敏感。0.1 μ M ITF2357可诱导AML1/ETO阳性原代母细胞和表达AML1/ETO的U937-A/E细胞凋亡，而非表达AML1/ETO的U937-A/E细胞无凋亡。在Kasumi-1细胞中，0.1 μ M ITF2357通过caspase依赖机制诱导AML1/ETO降解。ITF2357 0.1 μ M还测定了DNMT1从细胞核流出和p300向细胞核内流。此外，0.1 μ M ITF2357决定了局部H4乙酰化和DNMT1、HDAC1和AML1/ETO的释放，同时p300被募集到IL-3基因启动子上。然而，ITF2357处理没有诱导IL-3基因的重新表达。因此，IL-3启动子以及其他几个基因的甲基化水平未被改变。总之，ITF2357是一种抗白血病药物，对AML细胞，特别是AML1/ eto阳性细胞非常有效。更相关的是，我们的结果清楚地表明，ITF2357可能是治疗呈现AML1/ETO融合蛋白的AML亚型的理想药物，这种融合蛋白决定了HDAC参与白血病的发生。
We analysed the in vitro effects of a new hydroxamate derivative, ITF2357, on AML cells. ITF2357 potently induced histone acetylation. ITF2357 0.1 mu M blocked proliferation and induced apoptosis in AML1/ETO-positive Kasumi-1 cells, while AML1/ETO-negative HL60, THP1 and NB4 cell lines were sensitive only to 1 mu M ITF2357. Apoptosis was induced by 0.1 mu M ITF2357 in AML1/ETO-positive primary blasts and U937-A/E cells induced to express AML1/ETO, but not in U937-A/E cells non-expressing AML1/ETO. In Kasumi-1 cells 0.1 mu M ITF2357 induced AML1/ETO degradation through a caspase-dependent mechanism. ITF2357 0.1 mu M also determined DNMT1 efflux from, and p300 influx to, the nucleus. Moreover, 0.1 mu M ITF2357 determined local H4 acetylation and release of DNMT1, HDAC1 and AML1/ETO, paralleled by recruitment of p300 to the IL-3 gene promoter. ITF2357 treatment, however, did not induce re-expression of IL-3 gene. Accordingly, the methylation level of IL-3 promoter, as well as of several other genes, was unmodified. In conclusion, ITF2357 emerged as an antileukaemic agent very potent on AML cells, and on AML1/ETO-positive cells in particular. More relevantly, clearly emerged from our results that ITF2357 could be an ideal agent to treat AML subtypes presenting AML1/ETO fusion protein which determine HDAC involvement in leukaemogenesis.