全面分析急性髓系白血病中10-11易位蛋白（TETs）的表达及预后作用。
Comprehensively analyze the expression and prognostic role for ten-eleven translocations (TETs) in acute myeloid leukemia.
作者信息
Huang Yan, Wei Jie, Huang Xunjun, Zhou Weijie, Xu Yuling, Deng Dong-Hong, Cheng Peng
机构信息
Department of Hematology and Rheumatology, People's Hospital of Baise, Baise, China.
Department of Hematology, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.
出版信息
Transl Cancer Res. 2020 Nov;9(11):7259-7283. doi: 10.21037/tcr-20-3149.
BACKGROUND
The ten-eleven translocation (TET) family oxidize 5-methylcytosines (5mCs) and promote the locus-specific reversal of DNA. The role of TETs in acute myeloid leukemia (AML) is mostly unknown.
METHODS
TETs mRNA expression levels were analyzed via Gene Expression Profiling Interactive Analysis (GEPIA). The association TETs expression levels and methylation with prognosis by UALCAN GenomicScape, and METHsurv. We analyzed TETs' aberration types, located mutations, and structures via cBioPortal. GeneMANIA performed the functional network. Gene ontology (GO) enrichment was analyzed via LinkedOmics. MiWalK identified miRNAs, miTarbase, and TargetScan. Transcription factor (TF) targets were analyzed via ChEA3. GSCAlite analyzed the role of these defined genes in cancer pathways and potential drug targets. Finally, we selected AML patients in our department to investigate the mutated types of TETs.
RESULTS
TETs expression level results showed TET1 (P=0.003) and TET2 (P=0.004) overexpressed in Haferlach leukemia samples, TET3 (P=4.04e-8) downregulation in Andersson leukemia samples. TET2 and TET3 overexpression but TET1 downregulation in the GEPIA database. Overexpression of TET2 leads to positive outcomes (P=0.0091). The upregulation of TET2 led to poor survival for CN-AML patients, but downregulation of TET3 indicated a satisfactory prognosis. The hypermethylation of TETs like cg24705708 (P=0.036), cg05976228 (P=0.022), cg19127638 (P=0.022), cg15254238 (P=0.025), cg07669489 (P=0.037) indicate poor outcomes. Overexpression of GALNS (P=0.024) as an adverse biomarker, downregulation of E2F5 (P=0.037), MAP7 (P=0.019), and NRIP1 (P=0.0013) indicated good prognosis. Regulatory network analysis indicated TETs' functions, including covalent chromatin modification, histone modification, DNA methylation, or demethylation. Enrichment functions involving. TETs participate in several cancer pathways, including DNA repair response and receptor tyrosine kinase (RTK) signaling pathway. TETs are sensitive to belinostat, ceranib-2, docetaxel, tivantinib, and vincristine.
CONCLUSION
Present study showed that TETs have different expressions in AML, and the expression levels of TETs lead to different outcomes of AML. The TETs cancer pathway analysis will also provide potential therapy methods for AML patients with TETs aberrations.
背景
十一-易位（TET）家族可氧化5-甲基胞嘧啶（5mC），并促进位点特异性的DNA去甲基化。TET蛋白在急性髓系白血病（AML）中的作用大多未知。
方法
通过基因表达谱交互分析（GEPIA）分析TET蛋白的mRNA表达水平。利用UALCAN GenomicScape和METHsurv分析TET蛋白表达水平和甲基化与预后的关系。通过cBioPortal分析TET蛋白的畸变类型、定位突变和结构。使用GeneMANIA构建功能网络。通过LinkedOmics进行基因本体（GO）富集分析。利用MiWalK、miTarbase和TargetScan鉴定miRNA。通过ChEA3分析转录因子（TF）靶点。使用GSCAlite分析这些特定基因在癌症通路中的作用及潜在药物靶点。最后，选取本部门的AML患者研究TET蛋白的突变类型。
结果
TET蛋白表达水平结果显示，在Haferlach白血病样本中TET1（P = 0.003）和TET2（P = 0.004）过表达，在Andersson白血病样本中TET3（P = 4.04e - 8）下调。在GEPIA数据库中TET2和TET3过表达但TET1下调。TET2过表达导致阳性结果（P = 0.0091）。TET2上调导致CN - AML患者生存不良，但TET3下调提示预后良好。TET蛋白的高甲基化如cg24705708（P = 0.036）、cg05976228（P = 0.022）、cg19127638（P = 0.022）、cg15254238（P = 0.025）、cg07669489（P = 0.037）提示预后不良。GALNS过表达（P = 0.024）作为不良生物标志物，E2F5（P = 0.037）、MAP7（P = 0.019）和NRIP1（P = 0.0013）下调提示预后良好。调控网络分析表明TET蛋白的功能，包括共价染色质修饰 histone modification、DNA甲基化或去甲基化。富集功能涉及。TET蛋白参与多种癌症通路，包括DNA修复反应和受体酪氨酸激酶（RTK）信号通路。TET蛋白对贝利司他、西拉尼布 - 2、多西他赛、替凡替尼和长春新碱敏感。
结论
本研究表明TET蛋白在AML中表达不同，且TET蛋白的表达水平导致AML的不同预后。TET蛋白的癌症通路分析也将为有TET蛋白畸变的AML患者提供潜在的治疗方法。
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