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

Oncogene volume 37, pages 107–115 (2018)Cite this article

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Abstract

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.

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Acknowledgements

We acknowledge L Verboon, NJ Basheer and JM Boer for technical support and advice. This project was supported by grants from the Children Cancer Free Foundation (KIKA), project no. 64, entitled: Aberrant signal transduction profiling in pediatric AML.

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Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    N S D Larmonie, T C J M Arentsen-Peters, A Obulkasim, D Valerio, A A Danen-van Oorschot, C M Zwaan & M Fornerod

  2. Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands

    E Sonneveld & V de Haas

  3. Department of Pediatric Oncology/Hematology, Medical High School, Hannover, Germany

    D Reinhardt & M Zimmermann

  4. Pediatric Hematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic

    J Trka

  5. CHU de Paris-Hôpital Robert Debré, Paris, France

    A Baruchel

  6. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    R Pieters & M M van den Heuvel-Eibrink

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Larmonie, N., Arentsen-Peters, T., Obulkasim, A. et al. MN1 overexpression is driven by loss of DNMT3B methylation activity in inv(16) pediatric AML. Oncogene 37, 107–115 (2018). https://doi.org/10.1038/onc.2017.293

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