Abstract:
DNA methylation is a key epigenetic mechanism that is dysregulated in leukemia and plays a significant role in leukemogenesis. Ten-eleven translocation 2 (TET2) is one of the most frequently mutated genes among the DNA methylation regulators in hematologic malignancies, indicating its tumor-suppressor function. In this study, we investigated the expression and methylation status of TET2 in patients with AML. Quantitative RT-PCR was used to evaluate TET2 expression in peripheral blood mononuclear cells (PBMCs) from 51 newly diagnosed AML patients and 50 healthy controls. The methylation-sensitive high-resolution melting (MS-HRM) method was used in 45 patients with AML and 15 healthy controls to evaluate the promoter methylation of TET2. TET2 expression was significantly downregulated (P < 0.0001) in patients with AML compared to that in healthy controls. Furthermore, the methylation level of the TET2 promoter was significantly different between patients and controls. Aberrant methylation of the TET2 promoter was observed in 53.3% of the patients. Interestingly, a negative (- 0.3138) and significant (P = 0.0358) correlation between TET2 methylation and expression was found. The survival of patients with downregulated TET2 was poorer than that of other patients. TET2 gene expression was significantly downregulated while the promoter methylation was higher in patients, indicating that TET2 may be a tumor suppressor gene and a prognostic factor in AML and that transcriptional silencing of the TET2 gene may play a role in AML pathogenesis. Since epigenetic mechanisms are reversible, abnormal TET2 methylation could become a therapeutic target in the future.
摘要:
DNA甲基化是白血病中失调的关键表观遗传机制,在白血病发生中起着重要作用。十-十一易位2(TET2)是血液系统恶性肿瘤中DNA甲基化调节因子中最常见的突变基因之一。表明其肿瘤抑制功能。在这项研究中,我们研究了AML患者中TET2的表达和甲基化状态.采用定量RT-PCR方法评价51例初诊AML患者和50例健康对照者外周血单个核细胞(PBMC)中TET2的表达。采用甲基化敏感高分辨率熔解(MS-HRM)方法对45例AML患者和15例健康对照者进行TET2启动子甲基化评价。与健康对照组相比,AML患者的TET2表达显著下调(P<0.0001)。此外,TET2启动子的甲基化水平在患者和对照组之间有显著差异.在53.3%的患者中观察到TET2启动子的异常甲基化。有趣的是,发现TET2甲基化与表达之间存在负相关性(-0.3138)和显着相关性(P=0.0358)。TET2下调患者的生存率低于其他患者。患者TET2基因表达显著下调,而启动子甲基化水平较高,提示TET2可能是AML的抑癌基因和预后因子,TET2基因的转录沉默可能在AML发病机制中发挥作用.由于表观遗传机制是可逆的,TET2甲基化异常可能成为未来的治疗靶点。