title: Characterization of acute myeloid leukemia based on levels of global hydroxymethylation.
abstract: Patients with acute myeloid leukemia (AML) frequently harbor mutations in genes involved in the DNA (hydroxy)methylation pathway (DNMT3A, TET2, IDH1, and IDH2). In this study, we measured 5-hydroxymethylcytosine (5hmC) levels in 206 clinically and molecularly well-characterized younger adult AML patients (≤60 years) included in the European Organization for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche dell'Adulto (EORTC/GIMEMA) AML-12 06991 clinical trial and correlated the 5hmC levels with mutational status and overall survival (OS). In healthy control cells, 5hmC levels were confined to a narrow range (1.5-fold difference), whereas in AML cells, a much wider range was detected (15-fold difference). We identified 3 5hmC subpopulations in our patient cohort (low, intermediate, and high). The low 5hmC group consisted almost entirely of patients with TET2 or IDH mutations. As expected, TET2 and IDH mutated patients had significantly lower levels of 5hmC compared with patients without mutated TET2 and IDH1/2 (both P < .001). Interestingly, high 5hmC levels correlated with inferior OS (high vs intermediate 5hmC: P = .047, hazard ratio [HR] = 1.81). Multivariate analysis revealed that high 5hmC is an independent poor prognostic indicator for OS (high vs intermediate 5hmC: P = .01, HR = 2.10). This trial was registered at www.clinicaltrials.gov as NCT00004128.
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
authors.forename: Leonie I
authors.initials: LI
authors.lastname: Kroeze
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
authors.forename: Mariam G
authors.initials: MG
authors.lastname: Aslanyan
authors.affiliation: Department of Laboratory Medicine, Laboratory for Genetic, Endocrine, and Metabolic Diseases, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Arno
authors.initials: A
authors.lastname: van Rooij
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
authors.forename: Theresia N
authors.initials: TN
authors.lastname: Koorenhof-Scheele
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
authors.forename: Marion
authors.initials: M
authors.lastname: Massop
authors.affiliation: Department of Chemistry, Center for Integrated Protein Science Munich, Ludwig-Maximilians-University, Munich, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Carell
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
authors.forename: Jan B
authors.initials: JB
authors.lastname: Boezeman
authors.affiliation: Department Hematology and Tumor Bank, Saint-Antoine Hospital, 22 Assistance Publique-Hôpitaux de Paris and University Pierre and Marie Curie, Paris, France;
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marie
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Constantijn J M
authors.initials: CJ
authors.lastname: Halkes
authors.affiliation: Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
authors.forename: Theo
authors.initials: T
authors.lastname: de Witte
authors.affiliation: Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; and.
authors.forename: Gerwin
authors.initials: G
authors.lastname: Huls
authors.affiliation: European Organization for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.affiliation: Department of Laboratory Medicine, Laboratory for Genetic, Endocrine, and Metabolic Diseases, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
authors.forename: Bert A
authors.initials: BA
authors.lastname: van der Reijden
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A