A novel effect of DNA methyltransferase and histone deacetylase inhibitors -: NFκB inhibition in malignant myeloblasts
A novel effect of DNA methyltransferase and histone deacetylase inhibitors -: NFκB inhibition in malignant myeloblasts
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DOI：
10.4161/cc.7.14.6268
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发表时间：
2008-07-15
期刊：
影响因子：
4.3
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Fabre, Claire;Grosjean, Jennifer;Kroemer, Guido
高危骨髓增生异常综合征（MDS）和急性髓系白血病（AML）中产生的恶性成髓细胞以抗凋亡转录因子NF κ b的组成性激活为特征。我们发现DNA甲基转移酶（DNMT）抑制剂（如氮扎胞苷和5-aza-2'-脱氧胞苷）和组蛋白去乙酰化酶（HDAC）抑制剂（如曲古斯汀和丙戊酸）有效诱导P39 MDS/AML细胞系凋亡。与NF κ B（从细胞核转移到细胞质）的抑制相关。这种效果在几个小时内就能迅速获得，这表明它不是由于表观遗传重编程。事实上，DNMT和HDAC抑制剂降低了NF κ b活化激酶IKK α / β的磷酸化，并且在去核细胞中也观察到这种作用。最后，接受DNMT抑制剂5-aza-2'-脱氧胞苷治疗的AML患者的循环髓母细胞表现出NF κ B和IKK α / β的快速抑制（治疗后2小时）。综上所述，这些结果表明DNMT和HDAC抑制剂可以通过一种新机制在体外和体内抑制恶性成髓细胞NF κ B的组成性激活。
Malignant myeloblasts arising in high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the constitutive activation of the anti-apoptotic transcription factor NF kappa B. We found that DNA methyltransferase (DNMT) inhibitors (such as azacytidine and 5-aza-2'-deoxycytidine) and histone deacetylase (HDAC) inhibitors (such as trichostatin and valproic acid) efficiently induced apoptosis in the P39 MDS/AML cell line, correlating with an inhibition of NF kappa B (which translocated from the nucleus to the cytoplasm). This effect was obtained rapidly, within a few hours, suggesting that it was not due to epigenetic reprogramming. Indeed, DNMT and HDAC inhibitors reduced the phosphorylation of the NF kappa B-activating kinase IKK alpha/beta, and this effect was also observed in enucleated cells. Finally, circulating myeloblasts from AML patients treated with the DNMT inhibitor 5-aza-2'-deoxycytidine manifested a rapid (2 hours post-treatment) inhibition of NF kappa B and IKK alpha/beta. Altogether, these results indicate that DNMT and HDAC inhibitors can inhibit the constitutive activation of NF kappa B in malignant myeloblasts in vitro and in vivo through a novel mechanism.