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DNA methylation and hydroxymethylation patterns in acute myeloid leukemia patients with mutations in DNMT3A and IDH1/2 and their combinations
Š. Šestáková, Z. Krejčík, A. Folta, E. Cerovská, C. Šálek, MD. Merkerová, P. Pecherková, Z. Ráčil, J. Mayer, P. Cetkovský, H. Remešová,
Language English Country Netherlands
Document type Journal Article
Grant support
NV15-25809A
MZ0
CEP Register
Digital library NLK
Full text - Article
Source
NLK
Medline Complete (EBSCOhost)
from 2005-01-01 to 9 months ago
PubMed
30988238
DOI
10.3233/cbm-182176
Knihovny.cz E-resources
- MeSH
- Leukemia, Myeloid, Acute genetics metabolism MeSH
- DNA (Cytosine-5-)-Methyltransferases genetics MeSH
- Granzymes genetics MeSH
- Isocitrate Dehydrogenase genetics MeSH
- Leukocytes, Mononuclear metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Methylation * MeSH
- Mutation MeSH
- Prognosis MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Gene Expression Profiling MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Aberrant epigenetic patterns are a hallmark of acute myeloid leukemia (AML). Mutations in profound epigenetic regulators DNMT3A and IDH1/2 often occur concurrently in AML. OBJECTIVES: The aim was to analyze DNA methylation, hydroxymethylation and mRNA expression profiles in AML with mutations in DNMT3A and IDH1/2 (individually and in combinations). METHODS: Infinium MethylationEPIC BeadChip (Illumina) covering 850,000 CpGs was utilized. The validation of hydroxy-/methylation data was done by pyrosequencing. HumanHT-12 v4 Expression BeadChip (Illumina) was used for expression examination. RESULTS: Hierarchical clustering analysis of DNA hydroxy-/methylation data revealed clusters corresponding to DNMT3A and IDH1/2 mutations and CD34+ healthy controls. Samples with concurrent presence of DNMT3A and IDH1/2 mutations displayed mixed DNA hydroxy-/methylation profile with preferential clustering to healthy controls. Numbers and levels of DNA hydroxymethylation were low. Uniformly hypermethylated loci in AML patients with IDH1/2 mutations were enriched for immune response and apoptosis related genes, among which hypermethylation of granzyme B (GZMB) was found to be associated with inferior overall survival of AML patients (P= 0.035). CONCLUSIONS: Distinct molecular background results in specific DNA hydroxy-/methylation profiles in AML. Site-specific DNA hydroxymethylation changes are much less frequent in AML pathogenesis compared to DNA methylation. Methylation levels of enhancer located upstream GZMB gene might contribute to AML prognostication models.
Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic
Institute of Hematology and Blood Transfusion Prague Czech Republic
References provided by Crossref.org
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- $a BACKGROUND: Aberrant epigenetic patterns are a hallmark of acute myeloid leukemia (AML). Mutations in profound epigenetic regulators DNMT3A and IDH1/2 often occur concurrently in AML. OBJECTIVES: The aim was to analyze DNA methylation, hydroxymethylation and mRNA expression profiles in AML with mutations in DNMT3A and IDH1/2 (individually and in combinations). METHODS: Infinium MethylationEPIC BeadChip (Illumina) covering 850,000 CpGs was utilized. The validation of hydroxy-/methylation data was done by pyrosequencing. HumanHT-12 v4 Expression BeadChip (Illumina) was used for expression examination. RESULTS: Hierarchical clustering analysis of DNA hydroxy-/methylation data revealed clusters corresponding to DNMT3A and IDH1/2 mutations and CD34+ healthy controls. Samples with concurrent presence of DNMT3A and IDH1/2 mutations displayed mixed DNA hydroxy-/methylation profile with preferential clustering to healthy controls. Numbers and levels of DNA hydroxymethylation were low. Uniformly hypermethylated loci in AML patients with IDH1/2 mutations were enriched for immune response and apoptosis related genes, among which hypermethylation of granzyme B (GZMB) was found to be associated with inferior overall survival of AML patients (P= 0.035). CONCLUSIONS: Distinct molecular background results in specific DNA hydroxy-/methylation profiles in AML. Site-specific DNA hydroxymethylation changes are much less frequent in AML pathogenesis compared to DNA methylation. Methylation levels of enhancer located upstream GZMB gene might contribute to AML prognostication models.
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