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: Isabell Schulze, Christian Rohde, Marina Scheller-Wendorff, Nicole Bäumer, Annika Krause, Friederike Herbst, Pia Riemke, Katja Hebestreit, Petra Tschanter, Qiong Lin, Heinz Linhart, Lucy A Godley, Hanno Glimm, Martin Dugas, Wolfgang Wagner, Wolfgang E Berdel, Frank Rosenbauer, Carsten Müller-Tidow
• Journal: Blood (Blood) Vol. 127 Issue 12 Pg. 1575-86 (Mar 24 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 26729896 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• DNA (Cytosine-5-)-Methyltransferases

Topics

• Animals
• Carcinogenesis (genetics, pathology)
• DNA (Cytosine-5-)-Methyltransferases (genetics)
• DNA Methylation
• Gene Expression Regulation, Leukemic
• Gene Knock-In Techniques
• Hematopoiesis
• Humans
• Leukemia (diagnosis, genetics, pathology)
• Leukemia, Myeloid, Acute (diagnosis, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Neoplastic Stem Cells (metabolism, pathology)
• Prognosis
• Promoter Regions, Genetic
• DNA Methyltransferase 3B