title: Age-related epigenetic drift in the pathogenesis of MDS and AML.
abstract: The myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylation in the bone marrow and spleen in two mouse models of MDS/AML, the NUP98-HOXD13 (NHD13) mouse and the RUNX1 mutant mouse model. Methylation array analysis showed an average of 512/3445 (14.9%) genes hypermethylated in NHD13 MDS, and 331 (9.6%) genes hypermethylated in RUNX1 MDS. Thirty-two percent of genes in common between the two models (2/3 NHD13 mice and 2/3 RUNX1 mice) were also hypermethylated in at least two of 19 human MDS samples. Detailed analysis of 41 genes in mice showed progressive drift in DNA methylation from young to old normal bone marrow and spleen; to MDS, where we detected accelerated age-related methylation; and finally to AML, which markedly extends DNA methylation abnormalities. Most of these genes showed similar patterns in human MDS and AML. Repeat element hypomethylation was rare in MDS but marked the transition to AML in some cases. Our data show consistency in patterns of aberrant DNA methylation in human and mouse MDS and suggest that epigenetically, MDS displays an accelerated aging phenotype.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania 19140, USA;
authors.forename: Shinji
authors.initials: S
authors.lastname: Maegawa
authors.forename: Sheryl M
authors.initials: SM
authors.lastname: Gough
authors.forename: Naoko
authors.initials: N
authors.lastname: Watanabe-Okochi
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Castoro
authors.forename: Marcos R H
authors.initials: MR
authors.lastname: Estecio
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Shoudan
authors.initials: S
authors.lastname: Liang
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Peter D
authors.initials: PD
authors.lastname: Aplan
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D028861:Nuclear Pore Complex Proteins / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D028861:Nuclear Pore Complex Proteins; C493726:Runx1 protein, mouse; C093350:nuclear pore complex protein 98