Leukemogenic AML1-ETO fusion protein increases carcinogen-DNA adduct formation with upregulated expression of cytochrome P450-1A1 gene
Leukemogenic AML1-ETO fusion protein increases carcinogen-DNA adduct formation with upregulated expression of cytochrome P450-1A1 gene
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白血病 AML1-ETO 融合蛋白通过上调细胞色素 P450-1A1 基因的表达增加致癌物-DNA 加合物的形成
DOI：
10.1016/j.exphem.2007.04.018
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发表时间：
2007-08-01
影响因子：
2.6
通讯作者：
Chen, Guo-Qiang
中科院分区：
文献类型：
--
作者：
Xu, Min;Li, Dao;Chen, Guo-Qiang
Objective. AML 1-ETO融合蛋白是急性髓细胞白血病（AML）中常见的t（8;21）染色体易位产物，但其单独表达并不能引起明显的白血病。在这项研究中，我们调查了AML 1-ETO表达是否影响化学致癌物-DNA加合物的形成。在U937-A/E 9/14/18细胞中条件诱导AML 1-ETO融合蛋白。Western blot和/或定量RT-PCR检测多环芳烃（PAH）-DNA加合物的形成及PAH代谢酶细胞色素P450（CYP）1A 1和芳烃受体（AhR）的表达。荧光素酶报告系统检测AML 1-ETO对CYP 1A 1转录的调控。我们的研究结果表明，AML 1-ETO诱导显着增加致癌物苯并芘-DNA加合物在白血病细胞中的形成。与此一致，我们还发现，AML 1-ETO诱导上调CYP 1A 1的表达，这是依赖于在CYP 1A 1基因启动子的AML 1结合基序。此外，AML 1-ETO蛋白还可增加AhR的表达，AhR是一种配体激活的转录因子，介导PAH诱导的CYP 1A 1基因表达。这些数据，结合之前报道的对DNA修复的抑制作用，表明AML 1-ETO的存在增加了细胞对化学致癌物的易感性，这有利于其他遗传改变的发展。(c)2007 ISEH -血液学和干细胞学会。爱思唯尔公司出版
Objective. AML1-ETO fusion protein is a product of chromosome translocation t(8;21) frequently occurred in acute myeloid leukemia (AML), but its sole expression appears to fail to cause overt leukemia in vivo. In this study, we investigated whether AML1-ETO expression impinged on action of chemical carcinogens-DNA adduct formation.Materials and Methods. AML1-ETO fusion protein was conditionally induced in engineered U937-A/E 9/14/18 cells. The formation of polycyclic aromatic hydrocarbon (PAH)-DNA adducts and the expression of PAH-metabolizing enzymes cytochrome P450 (CYP) 1A1 and arythydrocarbon receptor (AhR) were detected by Western blot and/or quantitative RT-PCR. Luciferase reporter system was used to detect the regulation of AML1-ETO on CYP1A1 transcription.Results. Our results showed that AML1-ETO induction significantly increased the formation of carcinogen benzopyrene-DNA adducts in leukemic cells. In line with the effect, we also found that AML1-ETO induction upregulated CYP1A1 expression, which was dependent on AML1-binding motif in the promotor of CYP1A1 gene. Additionally, AML1-ETO protein also increased AhR expression, a ligand-activated transcription factor that mediates PAHsinduced CYP1A1 gene expression.Conclusion. These data, combined with its inhibitory effect on DNA repair as reported previously, propose that the presence of AML1-ETO increases the susceptibility of cells to chemical carcinogens, which favors the development of additional genetic alterations. (c) 2007 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.