title: Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia.
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.
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sonnet
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany ; Department of Hematology/Oncology, University Medical Center, D-79106 Freiburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Becker
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Lipka
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Oakes
authors.affiliation: Department of General Pathology, Institute of Pathology, University Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Lier
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Milsom
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Witte
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Soo-Zin
authors.initials: SZ
authors.lastname: Kim-Wanner
authors.affiliation: Department of General Pathology, Institute of Pathology, University Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, D-40225 Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wulfert
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, D-40225 Düsseldorf, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gattermann
authors.affiliation: Department of Hematology/Oncology, University Medical Center, D-79106 Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Institute of Molecular Tumor Biology, Westfälische Wilhelms Universität, D-48149 Münster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rosenbauer
authors.affiliation: Department of Hematology and Oncology, University Hospital Regensburg, D-93042 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rehli
authors.affiliation: Department of Internal Medicine III, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass