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Characterization of acute myeloid leukemia based on levels of global hydroxymethylation

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 and Joop H. Jansen

Key points

  • 5hmC levels vary considerably in patients with AML.

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

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 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 three 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 to patients without mutated TET2 and IDH1/2 (both P<.001). Interestingly, high 5hmC levels correlated with inferior OS (high vs intermediate 5hmC: P=.047, 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 ClinicalTrials.gov, identifier: NCT00004128.

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