title: Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome.
abstract: Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-2'-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease progression and how DNA methylation contributes to MDS remain unclear. We analyzed global DNA methylation in purified CD34+ hematopoietic progenitors from MDS patients undergoing multiple rounds of AZA treatment. Differential methylation between MDS phenotypes was observed primarily at developmental regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS patients. Haploinsufficiency in mice of one of these genes (NR4A2) has been shown to lead to excessive HSC proliferation, and our data suggest that suppression of NR4A2 by DNA methylation may be involved in MDS progression.
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan yan.fung.wong@sund.ku.dk mjakt@z2.keio.jp.
authors.forename: Yan-Fung
authors.initials: YF
authors.lastname: Wong
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan.
authors.forename: Chris N
authors.initials: CN
authors.lastname: Micklem
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Taguchi
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Itonaga
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sawayama
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Imanishi
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishikawa
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; The Danish Stem Cell Centre (DanStem), University of Copenhagen, Copenhagen, Denmark; Imperial College London, London, United Kingdom; All About Science Japan, Kobe, Japan; Department of Systems Medicine, Mitsunada Sakaguchi Laboratory, Keio University School of Medicine, Institute of Integrated Medical Research, Tokyo, Japan yan.fung.wong@sund.ku.dk mjakt@z2.keio.jp.
authors.forename: Lars Martin
authors.initials: LM
authors.lastname: Jakt
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D001374:Azacitidine / Q000627:therapeutic use; D019175:DNA Methylation / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008137:Longitudinal Studies; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics*; D016133:Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D018952:Antigens, CD34; D004791:Enzyme Inhibitors; D001374:Azacitidine
keywords: Azacytidine; DNA methylation; MDS; Myelodysplastic syndromes