Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia
Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia
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DOI：
10.1182/blood-2009-09-240978
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发表时间：
2010-11-04
期刊：
影响因子：
20.3
通讯作者：
Serve, Hubert
中科院分区：
文献类型：
--
作者：
Mueller-Tidow, Carsten;Klein, Hans-Ulrich;Serve, Hubert
急性髓系白血病(AML)通常与转录因子的改变有关，因为表达改变或基因突变。这些变化可能会诱导白血病特有的组蛋白修饰模式。我们用染色质免疫沉淀法分析了108例原发AML、28例急性淋巴细胞白血病、21例CD34(+)细胞和15例白细胞(n=15)的组蛋白3赖氨酸9三甲基化(H3K9me3)。AML中数百个启动子区域的H3K9me3水平发生了显著变化。在AML中，H3K9me3的失控主要发生在核心启动子区域H3K9me3水平的降低。改变的基因组区域显示了Ets的顺式结合位点和CREB/CREM/atf1家族转录因子的环磷酸腺苷反应元件(Cres)的过度表达。Cres中H3K9me3水平的降低与体内AML母细胞中Cre驱动的启动子活性的增加有关。AML特异性H3K9me3模式与已知的细胞遗传学异常无关。但是，来自H3K9me3模式的一个签名可以预测AML患者的无事件生存。当H3K9me3信号与已建立的临床预后标志物相结合时，其预后预测优于仅基于临床参数的预测。这些发现表明，H3K9me3基因启动子水平在AML中有广泛的变化。组蛋白修饰模式的特征与AML患者的预后有关。(血。2010；116(18)：3564-3571)
Acute myeloid leukemia (AML) is commonly associated with alterations in transcription factors because of altered expression or gene mutations. These changes might induce leukemia-specific patterns of histone modifications. We used chromatin-immunoprecipitation on microarray to analyze histone 3 lysine 9 trimethylation (H3K9me3) patterns in primary AML (n = 108), acute lymphoid leukemia (n = 28), CD34(+) cells (n = 21) and white blood cells (n = 15) specimens. Hundreds of promoter regions in AML showed significant alterations in H3K9me3 levels. H3K9me3 deregulation in AML occurred preferentially as a decrease in H3K9me3 levels at core promoter regions. The altered genomic regions showed an overrepresentation of cis-binding sites for ETS and cyclic adenosine monophosphate response elements (CREs) for transcription factors of the CREB/CREM/ATF1 family. The decrease in H3K9me3 levels at CREs was associated with increased CRE-driven promoter activity in AML blasts in vivo. AML-specific H3K9me3 patterns were not associated with known cytogenetic abnormalities. But a signature derived from H3K9me3 patterns predicted event-free survival in AML patients. When the H3K9me3 signature was combined with established clinical prognostic markers, it outperformed prognosis prediction based on clinical parameters alone. These findings demonstrate widespread changes of H3K9me3 levels at gene promoters in AML. Signatures of histone modification patterns are associated with patient prognosis in AML. (Blood. 2010; 116(18): 3564-3571)