Sonnet, Miriam and Claus, Rainer and Becker, Natalia and Zucknick, Manuela and Petersen, Jana and Lipka, Daniel B. and Oakes, Christopher C. and Andrulis, Mindaugas and Lier, Amelie and Milsom, Michael D. and Witte, Tania and Gu, Lei and Kim-Wanner, Soo-Zin and Schirmacher, Peter and Wulfert, Michael and Gattermann, Norbert and Luebbert, Michael and Rosenbauer, Frank and Rehli, Michael and Bullinger, Lars and Weichenhan, Dieter and Plass, Christoph (2014) Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia. GENOME MEDICINE, 6: 34. ISSN 1756-994X,
Full text not available from this repository. (Request a copy)Abstract
Background: Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. Methods: We screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylation levels of selected genes were correlated with methylation levels of CD34+ cells and lineage negative, CD127-, c-Kit+, Sca 1 + cells; common myeloid progenitors; granulocyte-macrophage progenitors; and megakaryocyte-erythroid progenitors. Results: We identified 1,184 hypermethylated array probes covering 762 associated genes in the preleukemic stage. During disease progression, the number of hypermethylated genes increased to 5,465 in the late leukemic disease stage. Using publicly available data, we found a significant enrichment of PU.1 binding sites in the preleukemic hypermethylated genes, suggesting that shortage of PU.1 makes PU.1 binding sites in the DNA accessible for aberrant methylation. Many known AML associated genes such as RUNX1 and HIC1 were found among the preleukemic hypermethylated genes. Nine novel hypermethylated genes, FZD5, FZD8, PRDM16, ROBO3, CXCL14, BCOR, ITPKA, HES6 and TAL1, the latter four being potential PU.1 targets, were confirmed to be hypermethylated in human normal karyotype AML patients, underscoring the relevance of the mouse model for human AML. Conclusions: Our study identified early aberrantly methylated genes as potential contributors to onset and progression of AML.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EMBRYONIC STEM-CELLS; TRANSCRIPTION FACTOR; PROMOTER HYPERMETHYLATION; GENE-EXPRESSION; TUMOR-NECROSIS; CANCER; PROGRESSION; CHEMOTHERAPY; PATHWAY; AML; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Nov 2019 14:18 |
| Last Modified: | 13 Nov 2019 14:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/10280 |
Actions (login required)
 |
View Item |
