mIDH-associated DNA hypermethylation in acute myeloid leukemia reflects differentiation blockage rather than inhibition of TET-mediated demethylation

Authors:

Laura Wiehle1, Günter Raddatz1, Stefan Pusch2,3, Julian Gutekunst1, Andreas von Deimling2,3, Manuel Rodríguez-Paredes1 and Frank Lyko1
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Affiliations:

1 Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center; 69120 Heidelberg, Germany.

2 German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

3 Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.

Keywords: 

mIDH, DNA methylation, AML, TET enzymes, differentiation, D-2-hydroxyglutarate.

Abbreviations:

2-HG – 2-hydroxyglutarate,

5hmC – 5-hydroxymethylcytosine,

AML – acute myeloid leukemia,

CIMP – CpG island methylator phenotype,

DMP – differentially methylated probe,

FAB – French-American-British,

IDH – isocitrate dehydrogenase,

LAD – lamina-associated domain,

mIDH – mutant IDH,

PCA – Principal Component Analysis.

Corresponding Author(s):

Frank Lyko, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; phone: +49-6221-423800; fax: +49-6221-423802 f.lyko@dkfz.de

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Laura Wiehle, Günter Raddatz, Stefan Pusch, Julian Gutekunst, Andreas von Deimling, Manuel Rodríguez-Paredes and Frank Lyko (2017). mIDH-associated DNA hypermethylation in acute myeloid leukemia reflects differentiation blockage rather than inhibition of TET-mediated demethylation. Cell Stress 1(1): 55-67. doi: 10.15698/cst2017.10.106

© 2017 Wiehle et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Isocitrate dehydrogenases 1 and 2 (IDH1/2) are recurrently mutated in acute myeloid leukemia (AML), but their mechanistic role in leukemogenesis is poorly understood. The inhibition of TET enzymes by D-2-hydroxyglutarate (D-2-HG), which is produced by mutant IDH1/2 (mIDH1/2), has been suggested to promote epigenetic deregulation during tumorigenesis. In addition, mIDH also induces a differentiation block in various cell culture and mouse models. Here we analyze the genomic methylation patterns of AML patients with mIDH using Infinium 450K data from a large AML cohort and found that mIDH is associated with pronounced DNA hypermethylation at tens of thousands of CpGs. Interestingly, however, myeloid leukemia cells overexpressing mIDH, cells that were cultured in the presence of D-2-HG or TET2 mutant AML patients did not show similar methylation changes. In further analyses, we also characterized the methylation landscapes of myeloid progenitor cells and analyzed their relationship to mIDH-associated hypermethylation. Our findings identify the differentiation state of myeloid cells, rather than inhibition of TET-mediated DNA demethylation, as a major factor of mIDH-associated hypermethylation in AML. Furthermore, our results are also important for understanding the mode of action of currently developed mIDH inhibitors.