Blood Journal
Leading the way in experimental and clinical research in hematology

Characterization of acute myeloid leukemia based on levels of global hydroxymethylation

  1. Leonie I. Kroeze1,
  2. Mariam G. Aslanyan1,
  3. Arno van Rooij2,
  4. Theresia N. Koorenhof-Scheele1,
  5. Marion Massop1,
  6. Thomas Carell3,
  7. Jan B. Boezeman1,
  8. Jean-Pierre Marie4,
  9. Constantijn J. M. Halkes5,
  10. Theo de Witte6,
  11. Gerwin Huls7,
  12. Stefan Suciu8,
  13. Ron A. Wevers2,
  14. Bert A. van der Reijden1, and
  15. Joop H. Jansen1,
  16. on behalf of the EORTC Leukemia Group and GIMEMA
  1. 1Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
  2. 2Department of Laboratory Medicine, Laboratory for Genetic, Endocrine, and Metabolic Diseases, Radboud University Medical Center, Nijmegen, The Netherlands;
  3. 3Department of Chemistry, Center for Integrated Protein Science Munich, Ludwig-Maximilians-University, Munich, Germany;
  4. 4Department Hematology and Tumor Bank, Saint-Antoine Hospital, 22 Assistance Publique-Hôpitaux de Paris and University Pierre and Marie Curie, Paris, France;
  5. 5Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;
  6. 6Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;
  7. 7Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; and
  8. 8European Organization for Research and Treatment of Cancer Headquarters, Brussels, Belgium

Key Points

  • 5hmC levels vary considerably in patients with AML.

  • High levels of 5hmC independently correlate with inferior overall survival in AML.


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 as NCT00004128.

  • Submitted August 2, 2013.
  • Accepted June 17, 2014.
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