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Blood. 2016 Mar 24;127(12):1575-86. doi: 10.1182/blood-2015-07-655928. Epub 2016 Jan 4.

Increased DNA methylation of Dnmt3b targets impairs leukemogenesis.

Author information

1
Department of Hematology and Oncology, University of Halle, Halle, Germany;
2
Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany;
3
National Center for Tumor Diseases, German Cancer Research Center Heidelberg, Heidelberg, Germany;
4
Institute of Molecular Tumor Biology and.
5
Institute of Medical Informatics, University of Münster, Münster, Germany;
6
Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; and.
7
Department of Medicine and Comprehensive Cancer Center, The University of Chicago, Chicago, IL.

Abstract

The de novo DNA methyltransferases Dnmt3a and Dnmt3b are of crucial importance in hematopoietic stem cells. Dnmt3b has recently been shown to play a role in genic methylation. To investigate how Dnmt3b-mediated DNA methylation affects leukemogenesis, we analyzed leukemia development under conditions of high and physiological methylation levels in a tetracycline-inducible knock-in mouse model. High expression of Dnmt3b slowed leukemia development in serial transplantations and impaired leukemia stem cell (LSC) function. Forced Dnmt3b expression induced widespread DNA hypermethylation inMyc-Bcl2-induced leukemias, preferentially at gene bodies.MLL-AF9-induced leukemogenesis showed much less pronounced DNA hypermethylation upon Dnmt3b expression. Nonetheless, leukemogenesis was delayed in both models with a shared core set of DNA hypermethylated regions and suppression of stem cell-related genes. Acute myeloid leukemia patients with high expression of Dnmt3b target genes showed inferior survival. Together, these findings indicate a critical role for Dnmt3b-mediated DNA methylation in leukemia development and maintenance of LSC function.

PMID:
26729896
DOI:
10.1182/blood-2015-07-655928
[Indexed for MEDLINE]
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