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5-Azacytidine Transiently Restores Dysregulated Erythroid Differentiation Gene Expression in TET2-Deficient Erythroleukemia Cells
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2020-11-10 , DOI: 10.1158/1541-7786.mcr-20-0453
Brian M Reilly 1, 2, 3 , Timothy Luger 2 , Soo Park 2 , Chan-Wang Jerry Lio 4 , Edahí González-Avalos 4 , Emily C Wheeler 1 , Minjung Lee 5 , Laura Williamson 6 , Tiffany Tanaka 2 , Dinh Diep 7 , Kun Zhang 7 , Yun Huang 5 , Anjana Rao 2, 4 , Rafael Bejar 1, 2
Affiliation  

DNA methyltransferase inhibitors (DNMTIs) like 5-Azacytidine (5-Aza) are the only disease-modifying drugs approved for the treatment of higher-risk myelodysplastic syndromes (MDS), however less than 50% of patients respond, and there are no predictors of response with clinical utility. Somatic mutations in the DNA methylation regulating gene tet-methylcytosine dioxygenase 2 (TET2) are associated with response to DNMTIs, however the mechanisms responsible for this association remain unknown. Using bisulfite padlock probes, mRNA sequencing, and hydroxymethylcytosine pull-down sequencing at several time points throughout 5-Aza treatment we show that TET2 loss particularly influences DNA methylation (5mC) and hydroxymethylation (5hmC) patterns at erythroid gene enhancers and is associated with down-regulation of erythroid gene expression in the human erythroleukemia cell line TF-1. 5-Aza disproportionately induces expression of these down regulated genes in TET2KO cells and this effect is related to dynamic 5mC changes at erythroid gene enhancers after 5-Aza exposure. We identified differences in remethylation kinetics after 5-Aza exposure for several types of genomic regulatory elements, with distal enhancers exhibiting longer-lasting 5mC changes than other regions. This work highlights the role of 5mC and 5hmC dynamics at distal enhancers in regulating the expression of differentiation-associated gene signatures, and sheds light on how 5-Aza may be more effective in patients harboring TET2 mutations. Implications: TET2 loss in erythroleukemia cells induces hypermethylation and impaired expression of erythroid differentiation genes which can be specifically counteracted by 5-Azacytidine, providing a potential mechanism for the increased efficacy of 5-Aza in TET2-mutant MDS patients.

中文翻译:

5-氮杂胞苷瞬时恢复 TET2 缺陷型红白血病细胞中失调的红细胞分化基因表达

5-氮杂胞苷 (5-Aza) 等 DNA 甲基转移酶抑制剂 (DNMTIs) 是唯一获批用于治疗高危骨髓增生异常综合征 (MDS) 的疾病缓解药物,但只有不到 50% 的患者有反应,而且没有预测因素具有临床效用的反应。DNA 甲基化调节基因 tet-甲基胞嘧啶双加氧酶 2 (TET2) 中的体细胞突变与对 DNMTI 的反应有关,但导致这种关联的机制仍然未知。使用亚硫酸氢盐挂锁探针,mRNA测序,和羟甲基胞嘧啶下拉测序在整个 5-Aza 处理的几个时间点,我们表明 TET2 缺失特别影响红细胞基因增强子的 DNA 甲基化 (5mC) 和羟甲基化 (5hmC) 模式,并且与红细胞基因表达的下调有关。人红白血病细胞系TF-1。5-Aza 不成比例地诱导 TET2KO 细胞中这些下调基因的表达,这种效应与 5-Aza 暴露后红系基因增强子的动态 5mC 变化有关。我们确定了几种类型的基因组调控元件在 5-Aza 暴露后再甲基化动力学的差异,远端增强子表现出比其他区域更持久的 5mC 变化。这项工作突出了远端增强子中 5mC 和 5hmC 动力学在调节分化相关基因特征表达中的作用,并阐明了 5-Aza 如何在携带 TET2 突变的患者中更有效。启示:红白血病细胞中的 TET2 缺失会诱导红细胞分化基因的高甲基化和受损表达,这可以被 5-氮杂胞苷特异性抵消,为 5-氮杂在 TET2 突变 MDS 患者中增加疗效提供了潜在机制。
更新日期:2020-11-10
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