分析 TET2 和 EZH2 基因在急性髓系白血病染色体不稳定性中的作用。

Analysis of TET2 and EZH2 gene functions in chromosome instability in acute myeloid leukemia.

机构信息

Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, P.R. China.

Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, P.R. China.

出版信息

Sci Rep. 2020 Feb 17;10(1):2706. doi: 10.1038/s41598-020-59365-w.

DOI:10.1038/s41598-020-59365-w

PMID:32066746

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7026035/

Abstract

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 fluorescence in situ hybridization (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.

摘要

TET2 和 EZH2 在许多癌症的表观遗传调控中发挥重要作用。然而，它们在急性髓系白血病（AML）发病机制中的具体作用尚不清楚。在这里，我们确定了 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 CDC20 的水平相关联。我们在 AML 细胞系中下调了 EZH2 和 TET2，并使用荧光原位杂交（FISH）评估了对 CIN 的影响。我们的结果表明，TET2、EZH2、MAD2 和 CDC20 在 AML 患者中异常表达。MAD2 或 CDC20 的表达水平与 TET2 或 EZH2 的表达水平呈正相关。TET2 基因的高甲基化下调了其转录。下调 EZH2 或 TET2 的表达抑制了细胞凋亡，影响了 MAD2 和 CDC20 的表达，并促进了 AML 细胞的 CIN。地西他滨治疗恢复了 TET2 的甲基化和 EZH2 的转录，并改善了 AML 中的 CIN。因此，TET2 和 EZH2 在 AML 中发挥抑癌作用，通过 MAD2 和 CDC20 影响 CIN。