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Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia

Leukemia volume 25, pages 1649–1652 (2011)Cite this article

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The TET proteins are 2-oxoglutarate- and Fe(II)-dependent oxygenase catalyzing the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).1 The TET1 (ten–eleven translocation 1) gene was originally identified as an MLL fusion partner in rare cases of acute myeloid leukemia (AML) with a t(10;11)(q22;q23).2, 3 The definite function of 5hmC still remains elusive, but hydroxylation of 5mC has been suggested to be involved in the process of DNA demethylation. This suggests a possible role of 5hmC in epigenetic gene regulation. Recently, hemizygous deletions and mutations of TET2 were found in a wide range of myeloid malignancies, including myelodysplastic syndrome (MDS), myeloproliferative disorders such as chronic myelomonocytic leukemia (CMML) and in secondary AML (sAML).4, 5, 6 Interestingly, very recently, myeloid neoplasias harboring heterozygous TET2 mutations were shown to have decreased levels of 5hmC.7

To explore the relationship among TET2 mutations, global gene expression profiles (GEPs) and 5hmC levels, we measured 5hmC levels in the genomic DNA in a series of 30 sAML patients using a novel assay method employing β-glucosyltransferase from bacteriophage T4.8 In addition to the TET2 mutational status, we screened for IDH1/2 mutations (see Supplementary Material).

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Acknowledgements

SKB, KS and HL are supported by grants from the Deutsche Forschungsgemeinschaft (SFB 684 and SPP 1463). SKB is supported by a grant from the German Ministry of Education and Research (BMBF) National genome research network (NGFNplus; PKL-01GS0876-6) and by institutional funding from the Helmholtz Zentrum Munich, German Research Center for Environmental Health. We thank Natalia Huk for technical assistance and Alexander Kohlmann, Torsten Haferlach and Claudia Haferlach for primary gene expression data and cytogenetic data.

Author Contributions

NK and FS designed and performed the mutation screening with the help of AD and BK, and wrote the manuscript. SB, AS and HL designed and performed the 5hmC measurements and wrote the manuscript. HL supervised the project. PMK and SS performed cytogenetics and fluorescence in situ hybridization analysis. TH and MM analyzed the GEPs. KS designed experiments and wrote the manuscript. SKB designed experiments, analyzed the data, supervised the project and wrote the manuscript.

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Author notes

  1. N Konstandin, S Bultmann, H Leonhardt and S K Bohlander: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine III, Laboratory of Leukemia Diagnostics, University of Munich Hospital, Munich, Germany

    N Konstandin, A Dufour, B Ksienzyk, F Schneider, T Herold, P M Kakadia, S Schneider, K Spiekermann & S K Bohlander

  2. Helmholtz Zentrum Munich, National Research Center for Environmental Health, Clinical Cooperative Group ‘Leukemia’, Munich, Germany

    N Konstandin, B Ksienzyk, F Schneider, M Mulaw, P M Kakadia, K Spiekermann & S K Bohlander

  3. Department of Biology II, Center for Integrated Protein Science, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany

    S Bultmann, A Szwagierczak & H Leonhardt

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  1. N Konstandin
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Corresponding authors

Correspondence to H Leonhardt or S K Bohlander.

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Supplementary Information accompanies the paper on the Leukemia website

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Konstandin, N., Bultmann, S., Szwagierczak, A. et al. Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia. Leukemia 25, 1649–1652 (2011). https://doi.org/10.1038/leu.2011.134

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