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. 2020 Jun 26;12(14):14677-14690.
doi: 10.18632/aging.103520. Epub 2020 Jun 26.

Expression and prognosis analysis of DNMT family in acute myeloid leukemia

Ting-Juan Zhang  1   2   3 , Liu-Chao Zhang  4 , Zi-Jun Xu  2   3   5 , Jing-Dong Zhou  1   2   3
Affiliations

Expression and prognosis analysis of DNMT family in acute myeloid leukemia

Ting-Juan Zhang et al. Aging (Albany NY). .

Abstract

DNA methyltransferases (DNMTs) by regulating DNA methylation play crucial roles in the progression of hematologic malignancies, especially for acute myeloid leukemia (AML). Accumulating investigations have identified the high incidence of DNMT3A mutation in AML, and it is correlated with poor prognosis. Although a few studies have shown the expression of DNMTs and their clinical significance in AML, the results remain to be discussed. Herein, we systemically analyzed the DNMTs expression and their relationship with clinic-pathological features and prognosis in AML patients. DNMTs expression especially for DNMT3A/3B was closely associated with AML among various human cancers. DNMT3A expression was increased in AML patients, whereas DNMT3B expression was decreased. Significant associations between DNMT3A/B expression and clinic-pathological features/gene mutations were observed. Kaplan-Meier analysis showed that DNMT3A expression was associated with better overall survival (OS) and leukemia-free survival (LFS) among whole-cohort AML, and independently affected OS determined by Cox repression multivariate analysis. Notably, patients that received hematopoietic stem cell transplantation (HSCT) showed significantly better OS and LFS in DNMT3A lower-expressed groups, whereas patients in DNMT3A higher-expressed groups did not. By bioinformatics analysis, DNMT3A expression was found to be positively correlated with several leukemia-associated genes/microRNAs, and DNMT3A was identified as direct targets of miR-429 and miR-29b in AML. Collectively, our study demonstrated that DNMT3A/3B showed significant expression differences in AML. DNMT3A expression acted as a potential prognostic biomarker and may guide treatment choice between chemotherapy and HSCT in AML.

Keywords: AML; DNMTs; HSCT; expression; prognosis.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that they have no conficts of interest.

Figures

Figure 1
Figure 1
The expression of DNMTs in human cancer cell lines including AML cell lines. (A) The expression of DNMTs in leukemia cell lines, analyzing by Cancer Cell Line Encyclopedia (CCLE) dataset. (B) The expression of DNMTs in leukemia cell lines, analyzing by The Human Protein Atlas (HPA) dataset. (C) The expression of DNMTs in leukemia cell lines, analyzed by European Bioinformatics Institute (EMBL-EBI) dataset.
Figure 2
Figure 2
The expression of DNMTs in human cancers including AML patients. (A) The expression of DNMTs in pan-cancer analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) web (http://gepia.cancer-pku.cn/). (B) The expression of DNMTs in AML analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) web (http://gepia.cancer-pku.cn/). (C) The correction between DNMTs in AML analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) web (http://gepia.cancer-pku.cn/).
Figure 3
Figure 3
The expression of DNMT3A and DNMT3B in AML patients with different molecular signature. The expression of DNMT3A in AML patients with and without NPM1 mutation as well as AML patients with and without DNMT3A mutation. The expression of DNMT3B in AML patients with and without IDH1 mutation as well as AML patients with and without TP53 mutation.
Figure 4
Figure 4
The impact of DNMTs expression on survival of AML patients. Kaplan–Meier survival curves of DNMTs expression on overall survival and leukemia-free survival in both chemotherapy and hematopoietic stem cell transplantation (HSCT) groups.
Figure 5
Figure 5
The effect of hematopoietic stem cell transplantation (HSCT) on survival of AML patients among different DNMT3A expression groups. Kaplan–Meier survival curves of overall survival and leukemia-free survival in low and high DNMT3A expression group.
Figure 6
Figure 6
Molecular signatures associated with DNMT3A in AML. (A) Volcano plot of differentially expressed genes between AML patients with low and high DNMT3A expression (FDR<0.05, P<0.05, and |log2 FC|>1.5). (B) Gene Ontology analysis of DEGs conducted using online website of STRING (http://string-db.org). (C) Expression heatmap of differentially expressed microRNAs between AML patients with low and high DNMT3A expression (FDR<0.05 and P<0.05). (D) Venn results of microRNAs which could target DNMT3A predicted by DIANA (http://diana.imis.athena-innovation.gr/DianaTools/index.php?r=microT_CDS/index), miRDB (http://mirdb.org/miRDB/), TargetScan (http://www.targetscan.org/vert_72/), miRDB (http://mirdb.org/), and starBase (http://www.sysu.edu.cn/403.html).
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