Base-Pair Resolution DNA Methylation Sequencing Reveals Profoundly Divergent Epigenetic Landscapes in Acute Myeloid Leukemia
Open accessAbstract
We have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from patients with Acute Myelogeneous Leukemia (AML), we demonstrated that genetically distinct AML subtypes display diametrically opposed DNA methylation patterns. As compared to normal controls, we observed widespread hypermethylation in IDH mutant AMLs, preferentially targeting promoter regions and CpG islands neighboring the transcription start sites of genes. In contrast, AMLs harboring translocations affecting the MLL gene displayed extensive loss of methylation of an almost mutually exclusive set of CpGs, which instead affected introns and distal intergenic CpG islands and shores. When analyzed in conjunction with gene expression profiles, it became apparent that these specific patterns of DNA methylation result in differing roles in gene expression regulation. However, despite this subtype-specific DNA methylation patterning, a much smaller set of CpG sites are consistently affected in both AML subtypes. Most CpG sites in this common core of aberrantly methylated CpGs were hypermethylated in both AML subtypes. Therefore, aberrant DNA methylation patterns in AML do not occur in a stereotypical manner but rather are highly specific and associated with specific driving genetic lesions.
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Variable methylation levels were observed globally in AML samples, and methylation at CpG islands was significantly higher in AML compared with normal PBMC and HSPC.
“We observed variable methylation levels globally in AML samples (Extended Data Fig. 11a) and significantly higher methylation at CpG islands in AML compared with normal PBMC and HSPC (Fig. 6a), consistent with previous findings46.”
From Subtype-specific 3D genome alteration in acute myeloid leukaemia (2022) · cites this paper as [46]
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- Authors
- Akalin, A., Garrett-Bakelman, F. E., Kormaksson, M., Busuttil, J., Zhang, L., Khrebtukova, I., Milne, T. A., Huang, Y., Biswas, D., Hess, J. L., Allis, C. D., Roeder, R. G., Valk, P. J. M., Löwenberg, B., Delwel, R., Fernandez, H. F., Paietta, E., Tallman, M. S., Schroth, G. P., Mason, C. E., Melnick, A., & Figueroa, M. E.
- Affiliations
- Cornell University (US)
- Weill Cornell Medicine (US)
- Illumina (United States) (US)
- University of Oxford (GB)
- University of Michigan (US)
- Rockefeller University (US)
- Erasmus MC (NL)
- Moffitt Cancer Center (US)
- Montefiore Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Mason, Christopher E.
- Melnick, Ari
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-06-21
- Volume
- 8
- Issue
- 6
- Pages
- e1002781
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3380828
- OpenAlex
- W2008420899
- Cited by
- 296
- References
- 53
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 13 · 2021: 21 · 2020: 24 · 2019: 15 · 2018: 21 · 2017: 26 · 2016: 27 · 2015: 31 · 2014: 41 · 2013: 39 · 2012: 11
- FWCI
- 15.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Leukemia and Lymphoma Society (7132-08)
- National Institutes of Health
- National Institute on Aging (P30AG013283)
- National Cancer Institute (R01CA151425, U24CA114737)
- National Institute of Neurological Disorders and Stroke (R01NS076465)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- DNA methylation, acute myeloid leukemia, reduced representation bisulfite sequencing, IDH mutation, MLL translocation, promoter hypermethylation, gene expression regulation, epigenetic heterogeneity, AML subtypes, bone marrow, CpG islands
- MeSH terms
- Base Sequence, Humans, Isocitrate Dehydrogenase, Molecular Sequence Data, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, Leukemia, Myeloid, Acute, Genome, Human, Gene Expression Regulation, Neoplastic, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Epigenesis, Genetic, HCT116 Cells, Myeloid-Lymphoid Leukemia Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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