| Literature DB >> 26729896 |
Isabell Schulze1, Christian Rohde1, Marina Scheller-Wendorff1, Nicole Bäumer2, Annika Krause2, Friederike Herbst3, Pia Riemke4, Katja Hebestreit5, Petra Tschanter1, Qiong Lin6, Heinz Linhart3, Lucy A Godley7, Hanno Glimm3, Martin Dugas5, Wolfgang Wagner6, Wolfgang E Berdel2, Frank Rosenbauer4, Carsten Müller-Tidow1.
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.Entities:
Mesh：
Substances：
Year: 2016 PMID： 26729896 DOI： 10.1182/blood-2015-07-655928
Source DB: PubMed Journal: Blood ISSN： 0006-4971 Impact factor: 22.113