Increased DNA methylation of Dnmt3b targets impairs leukemogenesis

• Published in: Blood Vol. 127; no. 12; pp. 1575 - 1586
• Main Authors: Schulze, Isabell, Rohde, Christian, Scheller-Wendorff, Marina, Bäumer, Nicole, Krause, Annika, Herbst, Friederike, Riemke, Pia, Hebestreit, Katja, Tschanter, Petra, Lin, Qiong, Linhart, Heinz, Godley, Lucy A., Glimm, Hanno, Dugas, Martin, Wagner, Wolfgang, Berdel, Wolfgang E., Rosenbauer, Frank, Müller-Tidow, Carsten
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24-03-2016
• Subjects: Animals; Carcinogenesis - genetics; Carcinogenesis - pathology; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation; DNA Methyltransferase 3B; Gene Expression Regulation, Leukemic; Gene Knock-In Techniques; Hematopoiesis; Humans; Leukemia - diagnosis; Leukemia - genetics; Leukemia - pathology; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Inbred C57BL; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prognosis; Promoter Regions, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-07-655928

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 in Myc-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.
•Increased gene body methylation inhibits leukemia, and oncogenes require varying levels of DNA methylation for efficient leukemogenesis.•Dnmt3b-induced DNA methylation in mice targets stem cell–associated genes with prognostic association in acute myeloid leukemia patients.