title: Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes.
abstract: The extent and role of aberrant DNA methylation in promoter CpG islands (CGIs) have been extensively studied in leukemia and other malignancies. Still, CGIs represent only a small fraction of the methylome. We aimed to characterize genome-wide differential methylation of cytogenetically normal AML (CN-AML) cells compared with normal CD34(+) bone marrow cells using the Illumina 450K methylation array. Differential methylation in CN-AML was most prominent in genomic areas far from CGIs, in so called open sea regions. Furthermore, differential methylation was specifically found in genes encoding transcription factors (TFs), with WT1 being the most differentially methylated TF. Among genetic mutations in AML, DNMT3A mutations showed the most prominent association with the DNA methylation pattern, characterized by hypomethylation of CGIs (as compared with DNMT3A wild type cases). The differential methylation in DNMT3A mutant cells vs. wild type cells was predominantly found in HOX genes, which were hypomethylated. These results were confirmed and validated in an independent CN-AML cohort. In conclusion, we show that, in CN-AML, the most pronounced changes in DNA methylation occur in non-CGI regions and that DNMT3A mutations confer a pattern of global hypomethylation that specifically targets HOX genes.
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM); Department of Medicine Huddinge; Karolinska Institute; Stockholm, Sweden.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Biosciences and Nutrition; NOVUM; Karolinska Institutet; Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lennartsson
authors.affiliation: Department of Internal Medicine III; University Hospital of Ulm; Ulm, Germany.
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM); Department of Medicine Huddinge; Karolinska Institute; Stockholm, Sweden; Hematology Centre, M54; Karolinska University Hospital and Karolinska Institute; Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Deneberg
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM); Department of Medicine Huddinge; Karolinska Institute; Stockholm, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM); Department of Medicine Huddinge; Karolinska Institute; Stockholm, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Bengtzén
authors.affiliation: Department of Hematology; Uppsala University Hospital; Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Höglund
authors.affiliation: Department of Internal Medicine III; University Hospital of Ulm; Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Internal Medicine III; University Hospital of Ulm; Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM); Department of Medicine Huddinge; Karolinska Institute; Stockholm, Sweden; Hematology Centre, M54; Karolinska University Hospital and Karolinska Institute; Stockholm, Sweden.
authors.forename: Sören
authors.initials: S
authors.lastname: Lehmann
mesh_terms: D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000378:metabolism; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005260:Female; D005801:Genes, Homeobox; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059467:Transcriptome; D025721:WT1 Proteins / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C000717967:DNMT3A protein, human; C493728:RUNX1 protein, human; D025721:WT1 Proteins; C583751:WT1 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNA methylation; DNMT3A; Homeobox gene family; acute myeloid leukemia; non-CGI region