| First Author | Schulze I | Year | 2016 |
| Journal | Blood | Volume | 127 |
| Issue | 12 | Pages | 1575-86 |
| PubMed ID | 26729896 | Mgi Jnum | J:232581 |
| Mgi Id | MGI:5779594 | Doi | 10.1182/blood-2015-07-655928 |
| Citation | mSchulze I, et al. (2016) Increased DNA methylation of Dnmt3b targets impairs leukemogenesis. Blood 127(12):1575-86 |
| abstractText | 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 ofDnmt3bslowed leukemia development in serial transplantations and impaired leukemia stem cell (LSC) function. ForcedDnmt3bexpression induced widespread DNA hypermethylation inMyc-Bcl2-induced leukemias, preferentially at gene bodies.MLL-AF9-induced leukemogenesis showed much less pronounced DNA hypermethylation uponDnmt3bexpression. 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. |
