Analysis of TET2 and EZH2 gene functions in chromosome instability in acute myeloid leukemia
Analysis of TET2 and EZH2 gene functions in chromosome instability in acute myeloid leukemia
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TET2和EZH2基因在急性髓系白血病染色体不稳定性中的功能分析
DOI：
10.1038/s41598-020-59365-w
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发表时间：
2020-02-17
影响因子：
4.6
通讯作者：
Ma, Daoxin
中科院分区：
文献类型：
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作者：
Wang, Jingyi;He, Na;Ma, Daoxin
TET2和EZH2在许多癌症的表观遗传调控中起重要作用。然而，它们在急性髓细胞白血病（AML）发病机制中的具体作用仍然未知。在此，确定EZH2和TET2的表达、甲基化或突变，并进一步与染色体不稳定性（CIN）基因MAD2和CDC 20的水平相关。我们在AML细胞系中下调EZH2和TET2，并使用荧光原位杂交（FISH）评估对CIN的影响。结果表明TET2、EZH2、MAD 2和CDC 20在AML患者中表达异常。MAD2、CDC20与TET2、EZH2的表达水平呈正相关。TET2基因的高甲基化下调其转录。EZH2或TET2表达下调可抑制AML细胞的凋亡，影响MAD 2和CDC 20的表达，并促进CIN。地西他滨治疗恢复TET2甲基化和EZH2转录，并改善AML中的CIN。因此，TET2和EZH2在AML中发挥肿瘤抑制作用，AML通过MAD 2和CDC 20影响CIN。
TET2 and EZH2 play important roles in the epigenetic regulation in many cancers. However, their specific roles in acute myeloid leukemia (AML) pathogenesis remain unknown. Here, the expression, methylation or mutation of EZH2 and TET2 was determined and further correlated with the levels of the chromosome instability (CIN) genes MAD2 and CDC20. We down-regulated EZH2 and TET2 in AML cell lines and assessed the effect on CIN using fluorescencein situhybridization (FISH). Our results showed that TET2, EZH2, MAD2 and CDC20 were aberrantly expressed in AML patients. The expression level of MAD2 or CDC20 was positively correlated with that of TET2 or EZH2. Hypermethylation of the TET2 gene down-regulated its transcription. Down-regulation of EZH2 or TET2 expression inhibited apoptosis, affected MAD2 and CDC20 expression, and promoted CIN in AML cells. Decitabine treatment restored TET2 methylation and EZH2 transcription and ameliorated CIN in AML. Therefore, TET2 and EZH2 play a tumor-inhibiting role in AML that affects CIN via MAD2 and CDC20.