Comprehensively analyze the expression and prognostic role for ten-eleven translocations (TETs) in acute myeloid leukemia

Yan Huang; Jie Wei; Xunjun Huang; Weijie Zhou; Yuling Xu; Dong-Hong Deng; Peng Cheng

doi:10.21037/tcr-20-3149

Comprehensively analyze the expression and prognostic role for ten-eleven translocations (TETs) in acute myeloid leukemia

Transl Cancer Res. 2020 Nov;9(11):7259-7283. doi: 10.21037/tcr-20-3149.

Authors

Yan Huang^#¹, Jie Wei^#¹, Xunjun Huang¹, Weijie Zhou¹, Yuling Xu², Dong-Hong Deng², Peng Cheng²

Affiliations

¹ Department of Hematology and Rheumatology, People's Hospital of Baise, Baise, China.
² Department of Hematology, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.

^# Contributed equally.

Abstract

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.

Keywords: Acute myeloid leukemia (AML); bioinformatics analysis; prognosis values; ten-eleven translocation (TETs).