Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene
Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene
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DOI：
10.1182/blood-2011-06-358705
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发表时间：
2012-03-08
期刊：
影响因子：
20.3
通讯作者：
Mueller-Tidow, Carsten
中科院分区：
文献类型：
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作者：
Agrawal-Singh, Shuchi;Isken, Fabienne;Mueller-Tidow, Carsten
在原代白血病样本的微阵列分析中使用ChIP，我们报告了急性髓性白血病（AML）原始细胞与CD 34（+）祖细胞相比，在> 1000个基因组位点处组蛋白H3乙酰化（H3 Ac）水平发生了显著变化。重要的是，与祖细胞相比，核心启动子区域在AML中倾向于具有较低的H3 Ac水平，这表明在AML中大量基因在表观遗传学上沉默。有趣的是，我们发现peroxiredoxin 2（PRDX 2）作为一种新的潜在的肿瘤抑制基因在AML。AML患者PRDX 2基因启动子区H3 Ac表达降低，与mRNA和蛋白表达降低相关。我们还观察到AML中PRDX 2启动子的DNA超甲基化。抗氧化剂PRDX 2基因的低蛋白表达在临床上与AML患者的不良预后相关。在功能上，PRDX 2通过降低响应于细胞因子而产生的活性氧（ROS）的水平而充当骨髓细胞生长的抑制剂。在小鼠骨髓移植中，强制PRDX 2表达抑制c-Myc诱导的体内白血病发生。总之，AML中H3 Ac的表观基因组范围分析导致PRDX 2被鉴定为表观遗传沉默的生长抑制因子，这表明ROS在AML的恶性表型中可能起作用。（血。2012;119（10）：2346-2357）
With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34(+) progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML. (Blood. 2012;119(10):2346-2357)