DNMT3A

Gene Summary

Gene:DNMT3A; DNA methyltransferase 3 alpha
Aliases: TBRS, DNMT3A2, M.HsaIIIA
Location:2p23.3
Summary:CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA (cytosine-5)-methyltransferase 3A
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
Show (27)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cohort Studies
  • Disease Progression
  • DNA (Cytosine-5-)-Methyltransferase 1
  • Transcriptional Activation
  • Isocitrate Dehydrogenase
  • Cell Proliferation
  • CpG Islands
  • Leukemic Gene Expression Regulation
  • Promoter Regions
  • Adolescents
  • Case-Control Studies
  • Genetic Predisposition
  • Xenograft Models
  • Chromosome 2
  • Disease-Free Survival
  • DNA Mutational Analysis
  • High-Throughput Nucleotide Sequencing
  • Antineoplastic Agents
  • Zinc Fingers
  • Hematopoiesis
  • Down-Regulation
  • Turkey
  • Precision Medicine
  • Young Adult
  • DNA Methylation
  • Neoplastic Cell Transformation
  • Breast Cancer
  • Biomarkers, Tumor
  • Ovarian Cancer
  • Myelodysplastic Syndromes
  • Gene Expression Profiling
  • Mutation
  • Acute Myeloid Leukaemia
  • Haematological Malignancies
  • Nuclear Proteins
  • DNA (Cytosine-5-)-Methyltransferases
  • Childhood Cancer
  • Cancer Gene Expression Regulation
  • DNA-Binding Proteins
  • Genotype
  • Epigenetics
  • Cell Movement
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DNMT3A (cancer-related)

Rashid M, van der Horst M, Mentzel T, et al.
ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.
Nat Commun. 2019; 10(1):2213 [PubMed] Free Access to Full Article Related Publications
Spiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma-spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A. Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.

Zhao L, Shou H, Chen L, et al.
Effects of ginsenoside Rg3 on epigenetic modification in ovarian cancer cells.
Oncol Rep. 2019; 41(6):3209-3218 [PubMed] Free Access to Full Article Related Publications
Epigenetic modifications are closely related to oncogene activation and tumor suppressor gene inactivation. The aim of this study was to determine the effects of ginsenoside Rg3 on epigenetic modification in ovarian cancer cells. Cell proliferation, metastasis, invasion and apoptosis were respectively determined using Cell Counting Kit‑8 (CCK‑8), wound healing, Transwell and flow cytometric assays. Methylation levels were determined using methylation specific PCR (MSP). Related‑factor expression was detected by conducting real‑time‑qPCR (RT‑qPCR) and western blotting. The results revealed that cell proliferation was inhibited by ginsenoside Rg3 (0, 25, 50, 100 and 200 µg/ml) in a time‑dependent manner (12, 24 and 48 h). Ginsenoside Rg3 (50, 100 and 200 µg/ml) was selected to treat cells in various experiments. When ovarian cells were treated with ginsenoside Rg3, cell apoptosis was observed to be promoted, while cell metastasis and invasion were inhibited at 48 h. The results of the present study revealed that in the promoter regions of p53, p16 and hMLH1, the methylation levels decreased, while the mRNA and protein levels significantly increased. The activities of DNMTs and mRNA as well as protein levels of DNMT1, DNMT3a and DNMT3b were decreased by Rg3. The data also demonstrated that the mRNA and protein levels of acetyl‑H3 K14/K9 and acetyl‑H4 K12/K5/K16 were increased by Rg3. Hence, ginsenoside Rg3 inhibited ovarian cancer cell viability, migration and invasion as well as promoted cell apoptosis.

Li Y, Lv X, Ge X, et al.
Mutational spectrum and associations with clinical features in patients with acute myeloid leukaemia based on next‑generation sequencing.
Mol Med Rep. 2019; 19(5):4147-4158 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to examine the associations between 112 acute myeloid leukaemia (AML)‑associated genes and the prognosis and clinical features of AML using bioinformatics analysis in 62 patients with AML. A total of 61 gene mutations were identified, and ≥1 mutations were detected in 96.77% of the patients. A total of 11 frequent mutations were identified, including nucleophosmin 1 (NPM1), Fms related tyrosine kinase 3 (FLT3), DNA methyltransferase 3α (DNMT3A) and Notch 2 (NOTCH2), with a mutation rate of ≥10%. The FLT3 mutation was significantly associated with the white blood cell count at the time of diagnosis, and DNMT3A was significantly associated with the French‑American‑British subtype and cytogenetics of patients with AML. The FLT3, NPM1 and DNMT3A mutations were significantly associated with a poor overall survival (OS) in patients with AML. In addition, the co‑mutation of DNMT3A‑CCAAT enhancer binding protein α (CEBPA) was observed to be significantly associated with a poor OS in patients with AML. Furthermore, the functional enrichment analysis revealed that the co‑mutations of FLT3‑NOTCH2, SETBP1‑CREBBP and DNMT3A‑CEBPA were significantly enriched in processes of 'negative regulation of cell differentiation' and 'immune system development', indicating that these mutations may serve crucial roles in the diagnosis and treatment of AML.

Sun J, Zhang J, Wang Y, et al.
A Pilot Study of Aberrant CpG Island Hypermethylation of
Int J Med Sci. 2019; 16(2):324-330 [PubMed] Free Access to Full Article Related Publications

Mao S, Zhang J, Guo Y, et al.
Hyperprogression after anti-programmed cell death ligand-1 therapy in a patient with recurrent metastatic urothelial bladder carcinoma following first-line cisplatin-based chemotherapy: a case report.
Drug Des Devel Ther. 2019; 13:291-300 [PubMed] Free Access to Full Article Related Publications
Background: Immune checkpoint blockade targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) signaling was approved recently for locally advanced and metastatic urothelial bladder carcinoma (UBC). Some patients experience a very rapid tumor progression, rather than clinical benefit, from anti-PD-L1/PD-1 therapy.
Case presentation: A 58-year-old male diagnosed with non-muscle-invasive bladder cancer 3 years ago received transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy. TURBT was repeated a year later for recurrent and progressive UBC. Following further disease progression, he received a radical cystectomy (RC), pathologically staged as T2bN2M0, and adjuvant cisplatin-containing combination chemotherapy. When his disease progressed to metastatic UBC, he was started on anti-PD-L1 monotherapy and experienced ultrarapid disease progression within 2 months; imaging scans ruled out pseudoprogression. We observed a fourfold increase in tumor growth rate, defined as the ratio of post- to pretreatment rates. Next-generation sequencing of formalin-fixed paraffin-embedded RC tissues showed
Conclusion: Even in cases with PD-L1-positive tumors,

Jang W, Park J, Kwon A, et al.
CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia.
Exp Mol Med. 2019; 51(1):4 [PubMed] Free Access to Full Article Related Publications
We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.

He D, Wang X, Zhang Y, et al.
DNMT3A/3B overexpression might be correlated with poor patient survival, hypermethylation and low expression of ESR1/PGR in endometrioid carcinoma: an analysis of The Cancer Genome Atlas.
Chin Med J (Engl). 2019; 132(2):161-170 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: DNA methylation is involved in numerous biologic events and associates with transcriptional gene silencing, playing an important role in the pathogenesis of endometrial cancer. ESR1/PGR frequently undergoes de novo methylation and loss expression in a wide variety of tumors, including breast, colon, lung, and brain tumors. However, the mechanisms underlying estrogen and progesterone receptors (ER/PR) loss in endometrial cancer have not been studied extensively. The aims of this study were to determine the expression of DNA (cytosine-5)-methyltransferase 3A/3B (DNMT3A/3B) in endometrial cancer to investigate whether the methylation catalyzed by DNMT3A/3B contributes to low ER/PR expression.
METHODS: The clinicopathologic information and RNA-Seq expression data of DNMT3A/3B of 544 endometrial cancers were derived from The Cancer Genome Atlas (TCGA) uterine cancer cohort in May 2018. RNA-Seq level of DNMT3A/3B was compared between these clinicopathologic factors with t-test or one-way analysis of variance.
RESULTS: DNMT3A/3B was overexpressed in endometrioid carcinoma (EEC) and was even higher in non-endometrioid carcinoma (NEEC) (DNMT3A, EEC vs. NEEC: 37.6% vs. 69.9%, t = -7.440, P < 0.001; DNMT3B, EEC vs. NEEC: 42.4% vs. 72.8%, t = -6.897, P < 0.001). In EEC, DNMT3A overexpression was significantly correlated with the hypermethylation and low expression of the ESR1 and PGR (P < 0.05). The same trend was observed in the DNMT3B overexpression subgroup. In the ESR1/PGR low-expression subgroups, as much as 83.1% of ESR1 and 59.5% of PGR were hypermethylated, which was significantly greater than the ESR1/PGR high-expression subgroups (31.3% and 11.9%, respectively). However, the above phenomena were absent in NEEC, while DNMT3A/3B overexpression, ESR1/PGR hypermethylation, and low ER/PR expression occurred much more often. In univariate analysis, DNMT3A/3B overexpressions were significantly correlated with worse prognosis. In multivariate analysis, only DNMT3A was an independent predictor of disease-free survival (P < 0.05).
CONCLUSIONS: DNMT3A/3B expression increases progressively from EEC to NEEC and is correlated with poor survival. The mechanisms underlying low ER/PR expression might be distinct in EEC vs. NEEC. In EEC, methylation related to DNMT3A/3B overexpression might play a major role in ER/PR downregulation.

Mochizuki D, Misawa Y, Kawasaki H, et al.
Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation.
Int J Mol Sci. 2018; 19(12) [PubMed] Free Access to Full Article Related Publications
Enhancer of Zeste homologue 2 (EZH2) overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibition of EZH2 is a potentially effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (

Zhou Z, Li HQ, Liu F
DNA Methyltransferase Inhibitors and their Therapeutic Potential.
Curr Top Med Chem. 2018; 18(28):2448-2457 [PubMed] Related Publications
Aberrant DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is associated with not only various cancers by silencing of tumor suppressor genes but also other diseases. The DNMTs, especially the DNMT1, DNMT3A and DNMT3B, are often overexpressed in various cancer tissues and cell lines. DNMTs are important epigenetic targets for drug development since the DNA methylation is reversible. This review summarizes an array of nucleoside and non-nucleoside inhibitors of DNMTs, as well as their biological activities. Among these inhibitors, the nucleoside analogue azacytidine and its deoxy derivative decitabine are both irreversible DNMT inhibitors and approved for the treatment of myelodysplastic syndrome.

Wu J, He K, Zhang Y, et al.
Inactivation of SMARCA2 by promoter hypermethylation drives lung cancer development.
Gene. 2019; 687:193-199 [PubMed] Related Publications
The SWI/SNF complex is a multimeric chromatin remodeling complex that has vital roles in regulating gene expression and cancer development. However, to date few studies have deeply explored the mechanism of SMARCA2 inactivation. We applied multi-omics analysis to explore the mechanism of SMARCA2 inactivation in The Cancer Genome Atlas (TCGA) database and performed the dCas9-DNMT3a system to evaluate the role of promoter methylation in SMARCA2 transcriptional regulation. We also assessed the tumor suppressing roles of SMARCA2 in lung cancer development by in vitro experiments. SMARCA2 promoter hypermethylation was significantly associated with decreased expression of SMARCA2. This result was further confirmed in the results of our own tissues. In addition, we observed that the mRNA level decreased by about 3 folds while the CpG island of promoter is nearly 30% hypermethylated by dCas9-DNMT3a system in H1299 cells. We identified SMARCA2 as a tumor suppressor gene whose expression was downregulated in lung cancers. Its inactivation was significantly associated with the poor survival of lung cancer patients [hazard ratio, HR = 0.35 (0.27-0.45)]. Besides, we found that SMARCA2 was a tumor suppressor and can significantly inhibit lung cancer cell vitality. We found that promoter hypermethylation contribute to the inactivation of SMARCA2. We also verified its oncogenetic roles of BRM inactivation in lung adenocarcinoma, which may provide a potential target for the clinical treatment.

Dumas PY, Mansier O, Prouzet-Mauleon V, et al.
MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms.
BMC Cancer. 2018; 18(1):1098 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since deregulation of microRNAs is involved in the biology of various cancers, we studied the miRNome of aMPN patients.
METHODS: MiRNome and mutations in epigenetic regulator genes ASXL1, TET2, DNMT3A, EZH2 and IDH1/2 were explored in aMPN patients. Epigenetic regulation of miR-10a and HOXB4 expression was investigated by treating hematopoietic cell lines with 5-aza-2'deoxycytidine, valproic acid and retinoic acid. Functional effects of miR-10a overexpression on cell proliferation, differentiation and self-renewal were studied by transducing CD34
RESULTS: MiR-10a was identified as the most significantly up-regulated microRNA in aMPN. MiR-10a expression correlated with that of HOXB4, sitting in the same genomic locus. The transcription of these two genes was increased by DNA demethylation and histone acetylation, both necessary for optimal expression induction by retinoic acid. Moreover, miR-10a and HOXB4 overexpression seemed associated with DNMT3A mutation in hematological malignancies. However, overexpression of miR-10a had no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors.
CONCLUSIONS: MiR-10a and HOXB4 are overexpressed in aMPN. This overexpression seems to be the result of abnormalities in epigenetic regulation mechanisms. Our data suggest that miR-10a could represent a simple marker of transcription at this genomic locus including HOXB4, widely recognized as involved in stem cell expansion.

Alvarez MC, Maso V, Torello CO, et al.
The polyphenol quercetin induces cell death in leukemia by targeting epigenetic regulators of pro-apoptotic genes.
Clin Epigenetics. 2018; 10(1):139 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In the present study, we investigated the molecular mechanisms underlying the pro-apoptotic effects of quercetin (Qu) by evaluating the effect of Qu treatment on DNA methylation and posttranslational histone modifications of genes related to the apoptosis pathway. This study was performed in vivo in two human xenograft acute myeloid leukemia (AML) models and in vitro using HL60 and U937 cell lines.
RESULTS: Qu treatment almost eliminates DNMT1 and DNMT3a expression, and this regulation was in part STAT-3 dependent. The treatment also downregulated class I HDACs. Furthermore, treatment of the cell lines with the proteasome inhibitor, MG132, together with Qu prevented degradation of class I HDACs compared to cells treated with Qu alone, indicating increased proteasome degradation of class I HDACS by Qu. Qu induced demethylation of the pro-apoptotic BCL2L11, DAPK1 genes, in a dose- and time-dependent manner. Moreover, Qu (50 μmol/L) treatment of cell lines for 48 h caused accumulation of acetylated histone 3 and histone 4, resulting in three- to ten fold increases in the promoter region of DAPK1, BCL2L11, BAX, APAF1, BNIP3, and BNIP3L. In addition, Qu treatment significantly increased the mRNA levels of all these genes, when compared to cells treated with vehicle only (control cells) (*p < 0.05).
CONCLUSIONS: In summary, our results showed that enhanced apoptosis, induced by Qu, might be caused in part by its DNA demethylating activity, by HDAC inhibition, and by the enrichment of H3ac and H4ac in the promoter regions of genes involved in the apoptosis pathway, leading to their transcription activation.

Magalhães L, Quintana LG, Lopes DCF, et al.
APC gene is modulated by hsa-miR-135b-5p in both diffuse and intestinal gastric cancer subtypes.
BMC Cancer. 2018; 18(1):1055 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Several genetic and epigenetic alterations are related to the development and progression of Gastric Cancer (GC), one of those being the deregulated microRNA (miRNA) expression profile. miRNAs are small noncoding RNAs that negatively regulate the expression of thousands of genes, including oncogenes and tumor suppressor genes. Our group identified, in previous studies, some miRNAs that are differentially expressed in GC when compared to the gastric mucosa without cancer, including hsa-miR-29c and hsa-miR-135b. The aim of the study was to modulate the expression of the miRNAs hsa-miR-29c-5p and hsa-miR-135b-5p and evaluate the expression of their target genes in 2D and 3D cell cultures.
METHODS: hsa-miR-29c-5p and hsa-miR-135b-5p expression profiles were modulated by transfecting mimics and antimiRs, respectively, in 2D and 3D cell cultures. The expression of the proteins coded by the genes CDC42, DNMT3A (target genes of hsa-miR-29c-5p) and APC (target gene of hsa-miR-135b-5p) were measured by Western Blot.
RESULTS: Results showed that mimics and antimiRs transfection significantly altered the expression of both miRNAs, increasing the expression of hsa-miR-29c-5p and reducing the expression of hsa-miR-135b-5p, especially in the 3D culture of the cell lines. When analyzing the proteins expression, we observed that AGP01 and AGP03 cell lines transfected with mimics had a reduction in the levels of CDC42 and DNMT3A and all three cell lines transfected with antimiRs had an increase in the expression of the protein APC.
CONCLUSION: We concluded that three-dimensional culture can be a more representative in vitro model that resembles better the in vivo reality. Our results also showed that hsa-miR-29c-5p is an important regulator of CDC42 and DNMT3A genes in the intestinal subtype gastric cancer and hsa-miR-135b-5p regulates the APC gene in both intestinal and diffuse subtypes of GC. Dysregulation in their expression, and consequently in their respectively signaling pathways, shows how these miRNAs can influence the carcinogenesis of different histological subtypes of gastric cancer.

Jacquelin S, Straube J, Cooper L, et al.
Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation.
Blood. 2018; 132(26):2707-2721 [PubMed] Related Publications
Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). We identify mutational cooperation between Jak2V617F expression and Dnmt3a loss that drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated protein 9 (Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC, we show that Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen. Transcriptional analysis and integration with human data sets identified a core DNMT3A-driven gene-expression program shared across multiple models and contexts of Dnmt3a loss. Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a

Jahangiri R, Jamialahmadi K, Gharib M, et al.
Expression and clinicopathological significance of DNA methyltransferase 1, 3A and 3B in tamoxifen-treated breast cancer patients.
Gene. 2019; 685:24-31 [PubMed] Related Publications
Progression of tamoxifen resistance remained as a crucial obstacle to treatment of estrogen receptor positive breast carcinoma patients. Recent studies demonstrated the importance of DNA methylation pattern on tamoxifen refractory. This study aimed to investigate the protein expression pattern and clinicopathological significance of DNA methyltransferase 1, 3A and 3B, as leading factors in regulation of DNA methylation process, in breast carcinoma patients with adjuvant tamoxifen therapy. Seventy two Formalin-Fixed Paraffin-Embedded (FFPE) breast tumor tissues of tamoxifen sensitive (TAMS) and tamoxifen resistance (TAM-R) patients were recruited for immunohistochemical experiments. DNMT1, DNMT3a, and DNMT3b expressions were observed in 86, 72.2 and 100% of tamoxifen resistance patients, respectively. Data analysis indicated that DNMTs were overexpressed in TAM-R tumors (P < 0.05). In TAM-S subgroup, DNMT1, DNMT3A and DNMT3B expression was associated with high histologic grade (P = 0.049, P = 0.01 and P = 0.02, respectively). DNMT3B expression was also correlated with lymphatic invasion (P = 0.034). In TAM-R subgroup, DNMT1 expression associated with extracapsular nodal extension (P = 0.019). DNMT3A and DNMT3B expression showed a significant association with high histologic grade (P = 0.001) and DNMT3A expression was also associated with HER-2 status (P = 0.027). Cox proportional hazard model demonstrated that overexpression of DNMT3B remained as an independent and unfavorable prognostic factor for disease free survival (P < 0.001). Taken together, these results suggest that DNMTs could be an effective factor in development of tamoxifen resistance in breast tumors.

Soda K
Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism.
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of

Yokoyama K, Shimizu E, Yokoyama N, et al.
Cell-lineage level-targeted sequencing to identify acute myeloid leukemia with myelodysplasia-related changes.
Blood Adv. 2018; 2(19):2513-2521 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) is a clonal myeloid neoplasm that typically arises de novo; however, some cases evolve from a preleukemic state, such as myelodysplastic syndrome (MDS). Such secondary AMLs and those with typical MDS-related clinical features are known as AMLs with myelodysplasia-related changes (AML-MRC). Because patients with AML-MRC have poor prognosis, more accurate diagnostic approaches are required. In this study, we performed targeted sequencing of 54 genes in 3 cell populations (granulocyte, blast, and T-cell fractions) using samples from 13 patients with MDS, 16 patients with clinically diagnosed AML-MRC, 4 patients with suspected AML-MRC but clinically diagnosed as AML not otherwise specified (AML-NOS), and 11 patients with de novo AML. We found that overlapping mutations, defined as those shared at least by the blast and granulocyte fractions, were significantly enriched in patients with MDS and AML-MRC, including those with suspected AML-MRC, indicating a substantial history of clonal hematopoiesis. In contrast, blast-specific nonoverlapping mutations were significantly enriched in patients with de novo AML. Furthermore, the presence of overlapping mutations, excluding

Döhner H, Dolnik A, Tang L, et al.
Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care.
Leukemia. 2018; 32(12):2546-2557 [PubMed] Free Access to Full Article Related Publications
Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m

Bera R, Chiu MC, Huang YJ, et al.
Genetic and Epigenetic Perturbations by DNMT3A-R882 Mutants Impaired Apoptosis through Augmentation of PRDX2 in Myeloid Leukemia Cells.
Neoplasia. 2018; 20(11):1106-1120 [PubMed] Free Access to Full Article Related Publications
DNA methyltransferase 3A (DNMT3A) is mutated in various myeloid neoplasms including acute myeloid leukemia (AML), especially at the Arg882 and associated with inferior outcomes. Here, we report that the DNMT3A-Arg882His/Cys (R882H/C) mutations led to inactivation of apoptosis through DNA damage signaling following the impairment of differentiation of myeloid leukemia cells. Gene expression profiling analysis revealed aberrant expression of several cell-cycle and apoptosis-related genes, and the DNA methylation assay identified both hypo- and hypermethylation features in different regions throughout the whole genome of DNMT3A mutants-transduced myeloid cells. We found that DNMT3A-R882H/C mutations upregulated the expression of an antioxidant protein, pyroxiredoxin-2 (PRDX2), at the mRNA and protein levels with decreased accumulation of reactive oxygen species (ROS). Augmentation of ROS generation by ROS accumulating agent or by knockdown of PRDX2 from myeloid cells effectively increased drug sensitivity and apoptosis as a consequence of reduced cell proliferation. DNMT3A-R882C/H mutations decreased apoptosis induction in part by increasing the antioxidant capacity of the cell owing to upregulation of PRDX2. Molecularly, both DNMT3A-WT and R882H/C mutants interacted with PRDX2; and R882C/H mutation-induced hypomethylation increased PRDX2 expression which enhanced cell proliferation and growth with impairment of apoptosis, thereby contributing to leukemogenesis.

Montes-Moreno S, Routbort MJ, Lohman EJ, et al.
Clinical molecular testing for ASXL1 c.1934dupG p.Gly646fs mutation in hematologic neoplasms in the NGS era.
PLoS One. 2018; 13(9):e0204218 [PubMed] Free Access to Full Article Related Publications
ASXL1 (additional sex combs like 1) is a gene that is mutated in a number of hematological neoplasms. The most common genetic alteration is c.1934dupG p.Gly646fs. Previous publications have shown that ASXL1 mutations have a negative prognostic impact in patients with MDS and AML, however, controversy exists regarding the molecular testing of ASXL1 c.1934dupG as polymerase splippage over the adjacent homopolymer could lead to a false-positive result. Here, we report the first study to systematically test different targeted next generation sequencing (NGS) approaches for this mutation in patients with hematologic neoplasms. In addition, we investigated the impact of proofreading capabilities of different DNA polymerases on ASXL1 c.1934dupG somatic mutation using conventional Sanger sequencing, another common method for ASXL1 genotyping. Our results confirm that ASXL1 c.1934dupG can be detected as a technical artifact, which can be overcome by the use of appropriate enzymes and library preparation methods. A systematic study of serial samples from 30 patients show that ASXL1 c.1934dupG is a somatic mutation in haematological neoplasms including MDS, AML, MPN and MDS/MPN and often is associated with somatic mutations of TET2, EZH2, IDH2, RUNX1, NRAS and DNMT3A. The pattern of clonal evolution suggests that this ASXL1 mutation might be an early mutational event that occurs in the principal clonal population and can serve as a clonal marker for persistent/relapsing disease.

Gao XN, Lin J, Wang SH, et al.
Donor lymphocyte infusion for prevention of relapse after unmanipulated haploidentical PBSCT for very high-risk hematologic malignancies.
Ann Hematol. 2019; 98(1):185-193 [PubMed] Free Access to Full Article Related Publications
Unmanipulated haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) has been an established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of treatment failure for patients with relapsed/refractory disease or with very high-risk gene mutations such as TP53, TET2, and DNMT3a. In this study, we aimed to establish the tolerance and efficacy of prophylactic donor lymphocyte infusion (DLI) with G-CSF-primed peripheral blood progenitors for prevention of relapse in these very high-risk patients after haplo-PBSCT. The prophylactic DLI was given at a median of 77 days after transplantation in 31 of 45 consecutive patients with very high-risk leukemia/lymphoma. The median dose of CD3

Khazayel S, Mokarram P, Mohammadi Z, et al.
Derivative of Stevioside; CPUK02; Restores ESR1 Gene Methylation in MDA-MB 231
Asian Pac J Cancer Prev. 2018; 19(8):2117-2123 [PubMed] Free Access to Full Article Related Publications
Background: CPUK02 (15-Oxosteviol benzyl ester) is a new ent-kaurenoid derivative of stevioside and exhibits strong anti-cancer activity. Nowadays, the pattern of epigenetic in cancer has been topic of many studies and DNA methylation targeting represents a relevant strategy for cancer treatment. Since, no study conducted to this mechanism, we attempt to evaluate whether CPUK02 induce its anti-cancer effects via alteration the level of mRNA DNMT3B, DNMT3A expression and ESR1 methylation pattern in breast cancer cells line. Methods: MCF-7 (ER +) and MDA-MB231 (ER-) cell lines were treated for 24, 48 hours with 1 μM CPUK02 and 5-AZA-CdR (DNA methyltransferase inhibitor). Quantitative expression of DNMT3B and DNMT3A genes and ESR1 promoter methylation was assessed by Real-Time PCR and MS-PCR, respectively. Results: CPUK02 restored ESR1 promoter unmethylated allele in MDA-MB 231 cells. Also treatment with CPUK02 decreased the expression of both DNMT3A and DNMT3B genes like 5-AZA. The expression of DNMT genes were diminished by half compared with control cells. Conclusions: These results showed that CPUK02 has an anticancer effect on MDA-MB 231 cells which this effect can be done through several pathways.

Donner I, Katainen R, Kaasinen E, et al.
Candidate susceptibility variants in angioimmunoblastic T-cell lymphoma.
Fam Cancer. 2019; 18(1):113-119 [PubMed] Related Publications
Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma with a poor prognosis: the 5-year survival rate is approximately 30%. Somatic driver mutations have been found in TET2, IDH2, DNMT3A, RHOA, FYN, PLCG1, and CD28, whereas germline susceptibility to AITL has to our knowledge not been studied. The homogenous Finnish population is well suited for studies on genetic predisposition. Here, we performed an exome-wide rare variant analysis in 23 AITL patients. No germline mutations were found in the driver genes, implying that they are not frequently involved in genetic AITL predisposition. Potentially pathogenic variants present in at least two patients and showing significant (p < 0.01) enrichment in our sample set were found in ten genes: POLK, PRKCB, ZNF676, PRRC2B, PCDHGB6, GNL3L, TTC36, OTOG, OSGEPL1, and RASSF9. The most significantly enriched variants, causing p.Lys469Ter in a splice variant of POLK and p.Pro588His in PRKCB, are intriguing candidates as Polk deficient mice display a spontaneous mutator phenotype, whereas PRKCB was recently shown to be somatically mutated in 33% of another peripheral T-cell lymphoma, adult T-cell lymphoma. If validated, our findings would provide new insight into the pathogenesis of AITL, as well as tools for early detection in susceptible individuals.

Su J, Huang YH, Cui X, et al.
Homeobox oncogene activation by pan-cancer DNA hypermethylation.
Genome Biol. 2018; 19(1):108 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancers have long been recognized to be not only genetically but also epigenetically distinct from their tissues of origin. Although genetic alterations underlying oncogene upregulation have been well studied, to what extent epigenetic mechanisms, such as DNA methylation, can also induce oncogene expression remains unknown.
RESULTS: Here, through pan-cancer analysis of 4174 genome-wide profiles, including whole-genome bisulfite sequencing data from 30 normal tissues and 35 solid tumors, we discover a strong correlation between gene-body hypermethylation of DNA methylation canyons, defined as broad under-methylated regions, and overexpression of approximately 43% of homeobox genes, many of which are also oncogenes. To gain insights into the cause-and-effect relationship, we use a newly developed dCas9-SunTag-DNMT3A system to methylate genomic sites of interest. The locus-specific hypermethylation of gene-body canyon, but not promoter, of homeobox oncogene DLX1, can directly increase its gene expression.
CONCLUSIONS: Our pan-cancer analysis followed by functional validation reveals DNA hypermethylation as a novel epigenetic mechanism for homeobox oncogene upregulation.

Sanders MA, Chew E, Flensburg C, et al.
MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.
Blood. 2018; 132(14):1526-1534 [PubMed] Free Access to Full Article Related Publications
The tendency of 5-methylcytosine (5mC) to undergo spontaneous deamination has had a major role in shaping the human genome, and this methylation damage remains the primary source of somatic mutations that accumulate with age. How 5mC deamination contributes to cancer risk in different tissues remains unclear. Genomic profiling of 3 early-onset acute myeloid leukemias (AMLs) identified germ line loss of MBD4 as an initiator of 5mC-dependent hypermutation. MBD4-deficient AMLs display a 33-fold higher mutation burden than AML generally, with >95% being C>T in the context of a CG dinucleotide. This distinctive signature was also observed in sporadic cancers that acquired biallelic mutations in

Martín I, Navarro B, Villamón E, et al.
Therapy-related acute myeloid leukemia developing 14 years after allogeneic hematopoietic stem cell transplantation, from a persistent R882H-DNMT3A mutated clone of patient origin.
Exp Mol Pathol. 2018; 105(1):139-143 [PubMed] Related Publications
BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) develops in patients with prior exposure to cytotoxic therapies. Selection of a pre-existing TP53 mutated clone prone to acquire additional mutational events has been suggested as the main pathogenic mechanism of t-AML. Here, we report a unique case of t-AML which developed from a pre-existing DNMT3A mutated clone that persisted in the patient for more than 10 years despite treatment with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (alloHSCT).
CASE PRESENTATION: A 42-year-old male was diagnosed with AML harboring a normal karyotype and mutations in the NPM1 (c.863_864ins, p.W288 fs*12), DNMT3A (c.2645G > A, p.R882H), and IDH1 (c.395G > A, p.R132H) genes. He achieved complete remission with intensive chemotherapy and was subsequently submitted to alloHSCT. Eleven years later, he was given chemotherapy and radiotherapy to treat a lung carcinoma. Three years later, t-AML was diagnosed; the disease had arisen from a pre-existing DNMT3A mutated patient-origin clone that had subsequently acquired a TP53 mutation and a complex karyotype. Although a second transplantation was intended, the disease was refractory to induction chemotherapy, and the patient eventually died from disease complications. We retrospectively demonstrated the persistence and post-transplantation latency of the R882H-DNMT3A mutation using a real-time PCR allele-specific analysis at different time-points during the observation period.
DISCUSSION AND CONCLUSION: The present case highlights the potential clinical implications of a R882H-DNMT3A mutated clone that persisted after conventional AML treatment, including alloHSCT. It also reinforces the notion of the importance of cell non-intrinsic factors, such as the hematopoietic-stress induced by chemotherapy and radiotherapy, as drivers of clonal expansion.

Ma HS, Wang EL, Xu WF, et al.
Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine-5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas.
Med Sci Monit. 2018; 24:4841-4850 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Alteration of DNA methylation of tumor suppressor genes (TSGs) is one of the most consistent epigenetic changes in human cancers. DNMTs play several important roles in DNA methylation and development of cancers. Regarding DNMTs protein expressions, little is known about the clinical significance and correlation with promoter methylation status of TSGs in human pituitary adenomas. MATERIAL AND METHODS We analyzed the protein expression of 3 DNMTs using immunohistochemistry and assessed DNA hypermethylation of RASSF1A, CDH13, CDH1, and CDKN2A (p16) in 63 pituitary adenomas. We examined associations between DNMTs expression and clinicopathological features or promoter methylation status of TSGs. RESULTS Overexpression of DNMTs was detected in pituitary adenomas. Frequencies of DNMT1 overexpression were significantly higher in macroadenomas, invasive tumors, and grade III and IV tumors. DNMT3A was frequently detected in invasive tumors and grade IV tumors. In addition, DNMT1 and DNMT3A were frequently detected in high-methylation tumors. Furthermore, in multivariate logistic regression, the significant association between DNMT1 or DNMT3A and high-methylation status persisted after adjusting for clinicopathological features. CONCLUSIONS Our findings suggested that tumor overexpression of DNMT1 and DNMT3A is associated with tumor aggressive behavior and high-methylation status in pituitary adenomas. Our data support a possible role of DNMT1 and DNMT3A in TSG promoter methylation leading to pituitary adenoma invasion and suggest that inhibition of DNMTs has the potential to become a new therapeutic approach for invasive pituitary adenoma.

Zhang S, Pei M, Li Z, et al.
Double-negative feedback interaction between DNA methyltransferase 3A and microRNA-145 in the Warburg effect of ovarian cancer cells.
Cancer Sci. 2018; 109(9):2734-2745 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is the most lethal gynecological malignancy because of its poor prognosis. The Warburg effect is one of the key mechanisms mediating cancer progression. Molecules targeting the Warburg effect are therefore of significant therapeutic value for the treatment of cancers. Many microRNAs (miR) are dysregulated in cancers, and aberrant miR expression patterns have been suggested to correlate with the Warburg effect in cancer cells. In our study, we found that miR-145 negatively correlated with DNA methyltransferase (DNMT)3A expression at cellular/histological levels. miR-145 inhibited the Warburg effect by targeting HK2. Luciferase reporter assays confirmed that miR-145-mediated downregulation of DNMT3A occurred through direct targeting of its mRNA 3'-UTRs, whereas methylation-specific PCR (MSP) assays found that knockdown of DNMT3A increased mRNA level of miR-145 and decreased methylation levels of promoter regions in the miR-145 precursor gene, thus suggesting a crucial crosstalk between miR-145 and DNMT3A by a double-negative feedback loop. DNMT3A promoted the Warburg effect through miR-145. Coimmunoprecipitation assays confirmed no direct binding between DNMT3A and HK2. In conclusion, a feedback loop between miR-145 and DNMT3A is a potent signature for the Warburg effect in ovarian cancer, promising a potential target for improved anticancer treatment.

Desai P, Mencia-Trinchant N, Savenkov O, et al.
Somatic mutations precede acute myeloid leukemia years before diagnosis.
Nat Med. 2018; 24(7):1015-1023 [PubMed] Related Publications
The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women's Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.

Gebhard C, Glatz D, Schwarzfischer L, et al.
Profiling of aberrant DNA methylation in acute myeloid leukemia reveals subclasses of CG-rich regions with epigenetic or genetic association.
Leukemia. 2019; 33(1):26-36 [PubMed] Related Publications
Malignant transformation is frequently associated with disease-specific epigenetic alterations, but the underlying mechanisms and pathophysiological consequences remain poorly understood. Here, we used global comparative DNA methylation profiling at CG-rich regions of 27 acute myeloid leukemia (AML) samples to select a subset of aberrantly methylated CG-rich regions (~400 regions, ~15,000 CpGs) for quantitative DNA methylation profiling in a large cohort of AML patients (n = 196) using MALDI-TOF analysis of bisulfite-treated DNA. Meta-analysis separated a subgroup of CG-rich regions showing highly correlated DNA methylation changes that were marked by histone H3 lysine 27 trimethylation in normal hematopoietic progenitor cells. While the group of non-polycomb group (PcG) target regions displayed methylation patterns that correlated well with molecular and cytogenetic markers, PcG target regions displayed a much weaker association with genetic features. However, the degree of methylation gain across the latter panel showed significant correlation with active DNMT3A levels and with overall survival. Our study suggests that both epigenetic as well as genetic aberrations underlay AML-related changes in DNA methylation at CG-rich regions and that the former may provide a marker to improve classification and prognostication of adult AML patients.

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