Epigenetic inactivation of the Groucho homologue gene TLE1 in hematologic malignancies
Epigenetic inactivation of the Groucho homologue gene TLE1 in hematologic malignancies
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DOI：
10.1158/0008-5472.can-08-0085
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Esteller, Manel
中科院分区：
文献类型：
--
作者：
Fraga, Mario F.;Berdasco, Maria;Esteller, Manel
未分化状态和肿瘤抑制基因的表观遗传失活是转化细胞的标志。然而，启动子CpG岛高甲基化的分化基因，很少有报道。Groucho同源物Transducin-like Enhancer of Split 1（TLE 1）是一种多任务转录辅阻遏物，通过急性髓细胞性白血病1、Wnt和Notch信号通路发挥作用。我们已经发现TLE 1经历启动子CpG岛高甲基化相关。在血液恶性肿瘤中，如弥漫性大B细胞淋巴瘤和AML中，我们还观察到TLE 1的表观遗传学改变和AML 1的细胞遗传学改变的相互排斥性。在高甲基化的白血病/淋巴瘤细胞中TLE 1的重新引入在集落测定和裸鼠中引起生长抑制，而在未甲基化的细胞中TLE 1短发夹RNA的耗尽增强肿瘤生长。我们还表明，这些影响介导的TLE 1转录抑制剂的活性，其靶基因，如细胞周期蛋白D1，集落刺激因子1受体，和分裂毛/增强子1。这些数据表明，TLE 1表观遗传失活有助于血液恶性肿瘤的发展，破坏关键分化和生长抑制途径。
An undifferentiated status and the epigenetic inactivation of tumor-suppressor genes are hallmarks of transformed cells. Promoter CpG island hypermethylation of differentiating genes, however, has rarely been reported. The Groucho homologue Transducin-like Enhancer of Split 1 (TLE1) is a multitasked transcriptional corepressor that acts through the acute myelogenous leukemia 1, Wnt, and Notch signaling pathways. We have found that TLE1 undergoes promoter CpG island hypermethylation-associated. inactivation in hematologic malignancies, such as diffuse large B-cell lymphoma and AML. We also observed a mutual exclusivity of the epigenetic alteration of TLE1 and the cytogenetic alteration of AML1. TLE1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas TLE1-short hairpin RNA depletion in unmethylated cells enhances tumor growth. We also show that these effects are mediated by TLE1 transcriptional repressor activity on its target genes, such as Cyclin D1, Colony-Stimulating Factor 1 receptor, and Hairy/Enhancer of Split 1. These data suggest that TLE1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting critical differentiation and growth-suppressing pathways.