A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells.
A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells.
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组蛋白乙酰转移酶 p300 抑制剂 C646 在 AML1-ETO 阳性 AML 细胞中选择性诱导细胞周期停滞和凋亡
DOI：
10.1371/journal.pone.0055481
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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：
Gao XN;Lin J;Ning QY;Gao L;Yao YS;Zhou JH;Li YH;Wang LL;Yu L
AML 1-ETO融合蛋白（AE）是由t（8;21）（q22;q22）染色体易位产生的，是急性髓系白血病（AML）中最常见的结构异常之一，在白血病的发生中起着关键作用。组蛋白乙酰转移酶p300通过乙酰化AE促进白血病细胞的自我更新，并作为转录共激活因子促进其下游基因的表达，这表明p300可能是AE阳性AML的潜在治疗靶点。然而，p300抑制剂对白血病细胞的作用及其机制尚未得到广泛研究。在本研究中，我们分析了选择性和竞争性p300抑制剂C646对AML细胞的抗白血病作用。结果表明，C646抑制细胞增殖，减少集落形成，诱发部分细胞周期停滞在G1期，并诱导凋亡的AE阳性AML细胞系和原代母细胞分离的白血病小鼠和AML患者。然而，在粒细胞集落刺激因子动员的正常外周血干细胞中没有观察到显著的抑制作用。值得注意的是，AE阳性AML细胞比AE阴性AML细胞对较低的C646剂量更敏感。C646对AE阳性AML细胞的生长抑制作用与组蛋白H3乙酰化水平降低、c-kit和bcl-2水平下降有关。因此，C646可能是治疗AE阳性AML的潜在候选药物。
AML1-ETO fusion protein (AE) is generated by t(8;21)(q22;q22) chromosomal translocation, which is one of the most frequently observed structural abnormalities in acute myeloid leukemia (AML) and displays a pivotal role in leukemogenesis. The histone acetyltransferase p300 promotes self-renewal of leukemia cells by acetylating AE and facilitating its downstream gene expression as a transcriptional coactivator, suggesting that p300 may be a potential therapeutic target for AE-positive AML. However, the effects of p300 inhibitors on leukemia cells and the underlying mechanisms have not been extensively investigated. In the current study, we analyzed the anti-leukemia effects of C646, a selective and competitive p300 inhibitor, on AML cells. Results showed that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients. Nevertheless, no significant inhibitory effects were observed in granulocyte colony-stimulating factor-mobilized normal peripheral blood stem cells. Notably, AE-positive AML cells were more sensitive to lower C646 doses than AE-negative ones. And C646-induced growth inhibition on AE-positive AML cells was associated with reduced global histone H3 acetylation and declined c-kit and bcl-2 levels. Therefore, C646 may be a potential candidate for treating AE-positive AML.
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DOI：
10.1073/pnas.1019625108
发表时间：
2011-02-08
影响因子：
11.1
作者：
Wang, Yue-Ying;Zhao, Li-Juan;Chen, Sai-Juan
通讯作者：
Chen, Sai-Juan
影响因子：
8
作者：
Iyer, N. G.;Xian, J.;Caldas, C.
通讯作者：
Caldas, C.
影响因子：
82.9
作者：
Linggi, B;Müller-Tidow, C;Hiebert, SW
通讯作者：
Hiebert, SW
影响因子：
4.8
作者：
Feng, LX;Ravindranath, N;Dym, M
通讯作者：
Dym, M
影响因子：
11.4
作者：
Kitabayashi, I;Aikawa, Y;Ohki, M
通讯作者：
Ohki, M