MN1 overexpression is driven by loss of DNMT3B methylation activity in inv(16) pediatric AML

In acute myeloid leukemia (AML), specific genomic aberrations induce aberrant methylation, thus directly influencing the transcriptional programing of leukemic cells. Therefore, therapies targeting epigenetic processes are advocated as a promising therapeutic tool for AML treatment. However, to deve...

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Bibliographic Details
Published in:Oncogene 2018-01, Vol.37 (1), p.107-115
Main Authors: Larmonie, N S D, Arentsen-Peters, T C J M, Obulkasim, A, Valerio, D, Sonneveld, E, Danen-van Oorschot, A A, de Haas, V, Reinhardt, D, Zimmermann, M, Trka, J, Baruchel, A, Pieters, R, van den Heuvel-Eibrink, M M, Zwaan, C M, Fornerod, M
Format: Article
Language:English
Subjects:
5-aza-2'-deoxycytidine
Acute myeloid leukemia
Adolescent
Azacitidine - analogs & derivatives
Azacitidine - pharmacology
Carcinogenesis - genetics
Cell Line, Tumor
Child
Child, Preschool
CpG islands
CpG Islands - genetics
Decitabine
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA methylation
DNA Methylation - drug effects
DNA Methylation - genetics
DNA Methyltransferase 3B
Epigenesis, Genetic - genetics
Epigenetics
Exons - genetics
Female
Gene Expression Regulation, Leukemic
Genomes
Humans
Infant
Infant, Newborn
Leukemia
Leukemia, Myeloid, Acute - blood
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - pathology
Leukemogenesis
Male
Meningioma
Myeloid leukemia
Nucleic Acid Hybridization - methods
Oligonucleotide Array Sequence Analysis - methods
Oncogene Proteins, Fusion - genetics
Pediatrics
Promoter Regions, Genetic - genetics
Trans-Activators
Transcription
Tumor Suppressor Proteins - genetics
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Summary:In acute myeloid leukemia (AML), specific genomic aberrations induce aberrant methylation, thus directly influencing the transcriptional programing of leukemic cells. Therefore, therapies targeting epigenetic processes are advocated as a promising therapeutic tool for AML treatment. However, to develop new therapies, a comprehensive understanding of the mechanism(s) driving the epigenetic changes as a result of acquired genetic abnormalities is necessary. This understanding is still lacking. In this study, we performed genome-wide CpG-island methylation profiling on pediatric AML samples. Six differentially methylated genomic regions within two genes, discriminating inv(16)(p13;q22) from non-inv(16) pediatric AML samples, were identified. All six regions had a hypomethylated phenotype in inv(16) AML samples, and this was most prominent at the regions encompassing the meningioma (disrupted in balanced translocation) 1 (MN1) oncogene. MN1 expression primarily correlated with the methylation level of the 3' end of the MN1 exon-1 locus. Decitabine treatment of different cell lines showed that induced loss of methylation at the MN1 locus can result in an increase of MN1 expression, indicating that MN1 expression is coregulated by DNA methylation. To investigate this methylation-associated mechanism, we determined the expression of DNA methyltransferases in inv(16) AML. We found that DNMT3B expression was significantly lower in inv(16) samples. Furthermore, DNMT3B expression correlated negatively with MN1 expression in pediatric AML samples. Importantly, depletion of DNMT3B impaired remethylation efficiency of the MN1 exon-1 locus in AML cells after decitabine exposure. These findings identify DNMT3B as an important coregulator of MN1 methylation. Taken together, this study shows that the methylation level of the MN1 exon-1 locus regulates MN1 expression levels in inv(16) pediatric AML. This methylation level is dependent on DNMT3B, thus suggesting a role for DNMT3B in leukemogenesis in inv(16) AML, through MN1 methylation regulation.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2017.293