Increased DNA methylation of Dnmt3b targets impairs leukemogenesis

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • DNA (Cytosine-5-)-Methyltransferases