Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication
The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. Motivated by a recent discovery of the significance of DNMT3A-destabilizing mutations (DNMT3A<sup>INS</sup>) in AML, we here investigate the common characteristics of DNMT3A<sup>INS</sup> AML methylomes through computational analyses. We present that methylomes of DNMT3A<sup>INS</sup> AMLs are considerably different from those of DNMT3A<sup>R882</sup> AMLs in that they exhibit increased intratumor DNA methylation heterogeneity in bivalent chromatin domains. This epigenetic heterogeneity was associated with the transcriptional variability of developmental and membrane-associated factors shaping stem cell niche, and also was a predictor of the response of AML cells to hypomethylating agents, implying that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions.
Authors
- Ja Min Byun (ORCID: https://orcid.org/0000-0003-1780-5553)
- Dong‐Yeop Shin (ORCID: https://orcid.org/0000-0003-1753-8846)
- Ji‐Joon Song (ORCID: https://orcid.org/0000-0001-7120-6311)
- Dohoon Lee (ORCID: https://orcid.org/0000-0003-2163-5489)
- Youngil Koh (ORCID: https://orcid.org/0000-0002-4750-931X)
- Bonil Koo (ORCID: https://orcid.org/0000-0003-4357-1850)
- Choong-Hyun Sun
- Junshik Hong (ORCID: https://orcid.org/0000-0002-7829-397X)
- Seokhyeon Kim (ORCID: https://orcid.org/0000-0002-1819-8022)
- Siddhartha Jaiswal (ORCID: https://orcid.org/0000-0002-9597-0477)
- Sun Kim (ORCID: https://orcid.org/0000-0001-5385-9546)
- Jaesung Kim (ORCID: https://orcid.org/0000-0001-8950-398X)
- Sung‐Soo Yoon (ORCID: https://orcid.org/0000-0003-2591-7459)
Institutions
- Seoul National University (KR)
- Korea Advanced Institute of Science and Technology (KR)
- Cancer Research Institute (US)
- Genome Research Foundation (KR)
- Seoul National University Hospital (KR)
- Genome and Company (South Korea) (KR)
- National University College (PR)
- Biotechnology Research Institute (CA)
- Institute of Refrigeration (GB)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-10
- DOI
- https://doi.org/10.1038/s41467-024-55691-z
- Citations
- 10
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- National Research Foundation
- Seoul National University
- Korea Health Industry Development Institute
- National Research Foundation of Korea
- Ministry of Science and ICT, South Korea
- Institute for Information and Communications Technology Promotion