Expression and prognosis analysis of TET family in acute myeloid leukemia.

Tingjuan Zhang,Jingdong Zhou,Yangli Zhao,Yangjing Zhao

doi:10.18632/aging.102928

Tingjuan Zhang, Jingdong Zhou + Show 2 more

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https://doi.org/10.18632/aging.102928

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Abstract

TET family members (TETs) encode proteins that represent crucial factors in the active DNA demethylation pathway. Evidence has proved that TET2 mutation is associated with leukemogenesis, drug response, and prognosis in acute myeloid leukemia (AML). However, few studies revealed the TETs expression and its clinical significance in AML. We conducted a detailed expression and prognosis analysis of TETs expression in human AML cell lines and patients by using public databases. We observed that TETs expression especially TET2 and TET3 was closely associated with AML among various human cancers. TET1 expression was significantly reduced in AML patients, whereas TET2 and TET3 expression was significantly increased. Kaplan-Meier analysis showed that only TET3 expression was associated with overall survival (OS) and disease-free survival (DFS) among both total AML as well as non-M3 AML, and was confirmed by another independent cohort. Moreover, Cox regression analysis revealed that TET3 expression may act as an independent prognostic factor for OS and DFS in total AML. Interestingly, patients that received hematopoietic stem cell transplantation (HSCT) did not show significantly longer OS and DFS than those who did not receive HSCT in TET3 high-expressed groups; whereas, in TET3 low-expressed groups, patients that accepted HSCT showed significantly longer OS and DFS than those who did not accept HSCT. By bioinformatics analysis, TET3 expression was found positively correlated with tumor suppressor gene including CDKN2B, ZIC2, miR-196a, and negatively correlated with oncogenes such as PAX2 and IL2RA. Our study demonstrated that TETs showed significant expression differences in AML, and TET3 expression acted as a potential prognostic biomarker in AML, which may guide treatment choice between chemotherapy and HSCT.

Highlights

DNA methylation has contributed to the understanding of the complexities of genomic instability and gene regulation without altering the DNA sequence [1]
By assembling the Cancer Cell Line Encyclopedia (CCLE), we found that Ten-eleven translocation (TET) expression especially TET2 and TET3 was highly expressed in acute myeloid leukemia (AML) cell lines among 40 types of human cancer cell lines (Figure 1A–1C)
TET1 expression was significantly reduced in AML patients, whereas TET2 and TET3 expression was significantly increased in AML patients (Figure 2D–2F)

Summary

INTRODUCTION

DNA methylation has contributed to the understanding of the complexities of genomic instability and gene regulation without altering the DNA sequence [1]. Aberrations in DNA methylation status are closely associated with tumor progression and prognosis of patients especially in blood cancers including acute myeloid leukemia (AML) [1, 2]. CpG islands in the promoter region of numerous genes become hypermethylated, silencing the expression of suppressor genes, and leading to a loss in the control of cell apoptosis, proliferation, and differentiation [1]. TET family members (TETs) were dysregulated in multiple malignances, and loss-of-function mutations or decreased expression of TETs inhibited the DNA demethylation pathway, which prevents the removal of 5mC from genomic DNA [5]. Rasmussen et al indicated that loss of TET2 in hematopoietic cells lead to DNA hypermethylation of active enhancers and induction of leukemogenesis [10]. We determined the clinical significance of TETs expression in AML among The Cancer Genome Atlas (TCGA) databases

RESULTS

DISCUSSION

MATERIALS AND METHODS

Ethical approval