DNA methylation and hydroxymethylation patterns in acute myeloid leukemia patients with mutations in DNMT3A and IDH1/2 and their combinations

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Authors

ŠESTÁKOVÁ Šárka KREJČÍK Zdeněk FOLTA Adam CEROVSKÁ Eva ŠÁLEK Cyril MERKEROVÁ DOSTÁLOVÁ Michaela PECHERKOVÁ Pavla RÁČIL Zdeněk MAYER Jiří CETKOVSKÝ Petr REMEŠOVÁ Hana

Year of publication 2019
Type Article in Periodical
Magazine / Source Cancer Biomarkers
MU Faculty or unit

Faculty of Medicine

Citation
Web http://dx.doi.org/10.3233/CBM-182176
Doi http://dx.doi.org/10.3233/CBM-182176
Keywords AML; DNMT3A and IDH1/2 mutations; methylation; hydroxymethylation; GZMB; CHFR
Description 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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