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

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 InteractiveAnalysis (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.

Complete hematologic response after belinostat treatment and allogeneic stem cell transplantation for multiple relapsed/refractory angioimmunoblastic T‐cell lymphoma: A case report

“…23 Using a gene set cancer analysis (GSCALite), both TET1 and TET2 genes were shown to be sensitive to belinostat. 26,27 Mutations in TET2 and RHOA were also present in our patient case, and the use of belinostat may have eventually led to a very good partial response of the disease, allowing an allo-SCT to be performed. A sub-analysis of the BELIEF study presented data from patients who underwent a hematopoietic SCT (HSCT) after belinostat treatment: a total of 12 patients, including two patients with nTFHL-AI, received either an ASCT (four patients) or an allo-SCT (eight patients).…”

“…It is suggested that HDAC inhibitors may help maintain an acetylated and active TET2 and therefore prevent the abnormal DNA methylation that occurs in cancer 23 . Using a gene set cancer analysis (GSCALite), both TET1 and TET2 genes were shown to be sensitive to belinostat 26,27 . Mutations in TET2 and RHOA were also present in our patient case, and the use of belinostat may have eventually led to a very good partial response of the disease, allowing an allo‐SCT to be performed.…”

Complete hematologic response after belinostat treatment and allogeneic stem cell transplantation for multiple relapsed/refractory angioimmunoblastic T-cell lymphoma: a case report

“…It is suggested that HDAC inhibitors may help maintain an acetylated and active TET2 and therefore prevent the abnormal DNA methylation that occurs in cancer 21 . Using a gene set cancer analysis (GSCALite), both TET1 andTET2 genes were shown to be sensitive to belinostat 23,24 . Mutations in TET2 andRHOA were also present in our patient case, and the use of belinostat may have eventually led to a very good partial response of the disease, allowing an allo-SCT to be performed.…”