title: Increased DNA methylation of Dnmt3b targets impairs leukemogenesis.
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.
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany;
authors.forename: Isabell
authors.initials: I
authors.lastname: Schulze
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Rohde
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany;
authors.forename: Marina
authors.initials: M
authors.lastname: Scheller-Wendorff
authors.affiliation: Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany;
authors.forename: Nicole
authors.initials: N
authors.lastname: Bäumer
authors.affiliation: Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany;
authors.forename: Annika
authors.initials: A
authors.lastname: Krause
authors.affiliation: National Center for Tumor Diseases, German Cancer Research Center Heidelberg, Heidelberg, Germany;
authors.forename: Friederike
authors.initials: F
authors.lastname: Herbst
authors.affiliation: Institute of Molecular Tumor Biology and.
authors.forename: Pia
authors.initials: P
authors.lastname: Riemke
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany;
authors.forename: Katja
authors.initials: K
authors.lastname: Hebestreit
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany;
authors.forename: Petra
authors.initials: P
authors.lastname: Tschanter
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; and.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: National Center for Tumor Diseases, German Cancer Research Center Heidelberg, Heidelberg, Germany;
authors.forename: Heinz
authors.initials: H
authors.lastname: Linhart
authors.affiliation: Department of Medicine and Comprehensive Cancer Center, The University of Chicago, Chicago, IL.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: National Center for Tumor Diseases, German Cancer Research Center Heidelberg, Heidelberg, Germany;
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; and.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wagner
authors.affiliation: Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany;
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Institute of Molecular Tumor Biology and.
authors.forename: Frank
authors.initials: F
authors.lastname: Rosenbauer
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany;
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D015973:Gene Expression Regulation, Leukemic; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B