MN1 overexpression is driven by loss of DNMT3B methylation activity in inv(16) pediatric AML
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
28892045
DOI
10.1038/onc.2017.293
PII: onc2017293
Knihovny.cz E-resources
- MeSH
- Leukemia, Myeloid, Acute blood genetics pathology MeSH
- Azacitidine analogs & derivatives pharmacology MeSH
- CpG Islands genetics MeSH
- Decitabine MeSH
- Child MeSH
- DNA (Cytosine-5-)-Methyltransferases metabolism MeSH
- DNA Methyltransferase 3B MeSH
- Epigenesis, Genetic genetics MeSH
- Exons genetics MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Nucleic Acid Hybridization methods MeSH
- Carcinogenesis genetics MeSH
- Infant MeSH
- Humans MeSH
- DNA Methylation drug effects genetics MeSH
- Adolescent MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Proteins genetics MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Promoter Regions, Genetic genetics MeSH
- Gene Expression Regulation, Leukemic * MeSH
- Oligonucleotide Array Sequence Analysis methods MeSH
- Trans-Activators MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Azacitidine MeSH
- Decitabine MeSH
- DNA (Cytosine-5-)-Methyltransferases MeSH
- Oncogene Proteins, Fusion MeSH
- inv(16) fusion protein, human MeSH Browser
- MN1 protein, human MeSH Browser
- Tumor Suppressor Proteins MeSH
- Trans-Activators MeSH
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.
CHU de Paris Hôpital Robert Debré Paris France
Department of Pediatric Oncology Hematology Medical High School Hannover Germany
Dutch Childhood Oncology Group The Hague The Netherlands
Pediatric Hematology Oncology 2nd Medical School Charles University Prague Czech Republic
Princess Maxima Center for Pediatric Oncology Utrecht The Netherlands
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