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Genome-wide analysis of focal DNA hypermethylation in IDH-mutant AML samples

Elisabeth R. Wilson, Nichole M. Helton, Sharon E. Heath, Robert S. Fulton, Jacqueline E. Payton, John S. Welch, Matthew J. Walter, Peter Westervelt, John F. DiPersio, Daniel C. Link, Christopher A. Miller, Timothy J. Ley, View ORCID ProfileDavid H. Spencer
doi: https://doi.org/10.1101/2021.03.03.433799
Elisabeth R. Wilson
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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Nichole M. Helton
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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Sharon E. Heath
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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Robert S. Fulton
3McDonnell Genome Institute, Washington University, St. Louis, MO, USA
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Jacqueline E. Payton
2Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
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John S. Welch
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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Matthew J. Walter
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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Peter Westervelt
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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John F. DiPersio
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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Daniel C. Link
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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Christopher A. Miller
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
3McDonnell Genome Institute, Washington University, St. Louis, MO, USA
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Timothy J. Ley
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
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David H. Spencer
1Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA
2Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
3McDonnell Genome Institute, Washington University, St. Louis, MO, USA
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  • ORCID record for David H. Spencer
  • For correspondence: dspencer@wustl.edu
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Abstract

Recurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4,000 focal regions that were uniquely hypermethylated vs. normal CD34+ cells. These regions had modest, but significant, hypermethylation in AMLs with biallelic TET2 mutations, and 5-hydroxymethylation levels that were dependent on functional TET2, indicating that hypermethylation in these regions is caused by inhibition of TET-mediated demethylation. Focal hypermethylation in IDHmut AMLs occurred in regions with low methylation in normal CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3AR882 mutations were significantly less hypermethylated, suggesting that methylation in these regions is mediated by DNMT3A. IDHmut-specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6. These results suggest that focal hypermethylation in IDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • The authors have no conflicts of interest relating to the work described in this manuscript.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Genome-wide analysis of focal DNA hypermethylation in IDH-mutant AML samples
Elisabeth R. Wilson, Nichole M. Helton, Sharon E. Heath, Robert S. Fulton, Jacqueline E. Payton, John S. Welch, Matthew J. Walter, Peter Westervelt, John F. DiPersio, Daniel C. Link, Christopher A. Miller, Timothy J. Ley, David H. Spencer
bioRxiv 2021.03.03.433799; doi: https://doi.org/10.1101/2021.03.03.433799
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Genome-wide analysis of focal DNA hypermethylation in IDH-mutant AML samples
Elisabeth R. Wilson, Nichole M. Helton, Sharon E. Heath, Robert S. Fulton, Jacqueline E. Payton, John S. Welch, Matthew J. Walter, Peter Westervelt, John F. DiPersio, Daniel C. Link, Christopher A. Miller, Timothy J. Ley, David H. Spencer
bioRxiv 2021.03.03.433799; doi: https://doi.org/10.1101/2021.03.03.433799

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