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: Leonie I Kroeze, Mariam G Aslanyan, Arno van Rooij, Theresia N Koorenhof-Scheele, Marion Massop, Thomas Carell, Jan B Boezeman, Jean-Pierre Marie, Constantijn J M Halkes, Theo de Witte, Gerwin Huls, Stefan Suciu, Ron A Wevers, Bert A van der Reijden, Joop H Jansen, EORTC Leukemia Group and GIMEMA
• Journal: Blood (Blood) Vol. 124 Issue 7 Pg. 1110-8 (Aug 14 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24986689 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• DNA-Binding Proteins
• DNMT3A protein, human
• Proto-Oncogene Proteins
• 5-hydroxymethylcytosine
• 5-Methylcytosine
• Cytosine
• Isocitrate Dehydrogenase
• Dioxygenases
• TET2 protein, human
• DNA (Cytosine-5-)-Methyltransferases
• DNA Methyltransferase 3A

Topics

• 5-Methylcytosine (analogs & derivatives)
• Acute Disease
• Adolescent
• Adult
• Aged
• Cytosine (analogs & derivatives, metabolism)
• DNA (Cytosine-5-)-Methyltransferases (genetics)
• DNA Methylation (genetics)
• DNA Methyltransferase 3A
• DNA Mutational Analysis
• DNA-Binding Proteins (genetics)
• Dioxygenases
• Humans
• Isocitrate Dehydrogenase (genetics)
• Leukemia, Myeloid (genetics, metabolism, pathology)
• Middle Aged
• Mutation
• Prognosis
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Proteins (genetics)
• Survival Analysis
• Young Adult