Clinical Significance Of TET2Gene Expression In Adult Cytogenetically Normal Acute Myeloid Leukemia

Object:To explore the clinical significance of the expression levels of TET2mRNA in cytogenetically normal acute myeloid leukemia (CN-AML).Methods:Expression level of TET2mRNA was measured in primary bone marrow mononuclear cells of157CN-AML patients, bone marrow CD34+of10healthy controls and8healthy controls by real-time PCR. Gene mutation status of NMP1, FLT3-ITD, IDH1, IDH2, DNMT3A and CEBPA were sequenced as well. Factos associated with TET2mRNA level and the probabilities of overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS) were evaluated by using the SPSS16.0.The impact of multiple predictor variables on OS, EFS and RFS was analyzed, too. We also assessed TET2expression change between at primary diagnosis and at complete remission. After down-regulation TET2by small interfering RNA (siRNA) for48h, cell growth, colony formation and sensitivity to decitabine (DAC) were observed. Results:(1) TET2mRNA expression level of AML CD34+cells was significantly lower than that of healthy control (p=0.03).(2) In17pared CN-AML, TET2mRNA level at diagnosis was obviously lower than that at complete remission (p<0.001).(3) In CN-AML, there were no association between TET2gene expression and clinical parameters. However, patients with mutant CEBPA showed lower TET2mRNA level than that with wild CEBPA (p=0.003), while patients with mutant DNMT3A or NPM1both displayed higher TET2gene expression than that with wild (p=0.023and p=0.026, respectively).(4) In157de novo CN-AML, patients with lower TET2gene expression had shorter OS than that with higher TET2expression (p=0.041). The median OS was295days and445days, respectively.(5) In CN-AML, CEBPA (+)/TET2high expression patients had longer EFS than CEBPA (+)/TET2low expression or CEBPA (-) patients (p=0.027), while DNMT3A (-)/TET2high expression patients had longer OS and EFS than DNMT3A (-)/TET2low expression patients or DNMT3A (+) patients (p=0.002and0.015, respectively).(6) After adjusting the impact of age, WBC and gene mutations by Backward LR Cox model in157de novo CN-AML patients, lower TET2gene expression had an independent prognostic value for a shorter OS and EFS (HR:0.513and0.418, p values were0.006and0.038, respectively). In multivariate analysis, lower TET2gene expression was an independent predictor for a shorter survival.(7) In104de novo CN-AML patients without CEBPA double-mutation or DNMT3A mutation, lower TET2gene expression was significantly associated with shorter OS and EFS (p=0.013and p=0.041, respectively). (8) After inhibited by decitabine, the expression of TET2in THP-1and Kasumi increased with decitabine concentration.(9) Afte down-regulation TET2expression, THP-1cell showed increased colony formation and decreased sensitivity to DAC than that of negative control.Conclusion:(1) Low TET2gene expression is an independent adverse prognostic factor in CN-AML, especially in CEBPA (-)/DNMT3A (-) subgroup, and could improve the molecular-based risk stratification in CN-AML.(2) TET2gene may plays an anti-leukemia role in AML, and its aberrant low expression may an early event in leukemogenesis(3) TET2may be involved in decitabine’s antileukemia mechanism.