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Acute myeloid leukemia

Profiling of aberrant DNA methylation in acute myeloid leukemia reveals subclasses of CG-rich regions with epigenetic or genetic association

Abstract

Malignant transformation is frequently associated with disease-specific epigenetic alterations, but the underlying mechanisms and pathophysiological consequences remain poorly understood. Here, we used global comparative DNA methylation profiling at CG-rich regions of 27 acute myeloid leukemia (AML) samples to select a subset of aberrantly methylated CG-rich regions (~400 regions, ~15,000 CpGs) for quantitative DNA methylation profiling in a large cohort of AML patients (n = 196) using MALDI-TOF analysis of bisulfite-treated DNA. Meta-analysis separated a subgroup of CG-rich regions showing highly correlated DNA methylation changes that were marked by histone H3 lysine 27 trimethylation in normal hematopoietic progenitor cells. While the group of non-polycomb group (PcG) target regions displayed methylation patterns that correlated well with molecular and cytogenetic markers, PcG target regions displayed a much weaker association with genetic features. However, the degree of methylation gain across the latter panel showed significant correlation with active DNMT3A levels and with overall survival. Our study suggests that both epigenetic as well as genetic aberrations underlay AML-related changes in DNA methylation at CG-rich regions and that the former may provide a marker to improve classification and prognostication of adult AML patients.

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Acknowledgements

We thank Johanna Raithel for excellent technical assistance. This work was funded by grants from the Wilhelm Sander Foundation and the German Cancer Aid to MR.

Author contributions

CG, RA, and MR designed research; CG, DG, LS, JW, SS, DH, and MN performed research; GE and CT contributed clinical samples, new reagents, or analytic tools; CG and MR analyzed data; CG and MR wrote the paper.

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CT is part owner and CEO of AgenDix GmbH. The remaining authors declare that they have no conflict of interest.

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Gebhard, C., Glatz, D., Schwarzfischer, L. et al. Profiling of aberrant DNA methylation in acute myeloid leukemia reveals subclasses of CG-rich regions with epigenetic or genetic association. Leukemia 33, 26–36 (2019). https://doi.org/10.1038/s41375-018-0165-2

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