Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication

Dohoon Lee, Bonil Koo, Seokhyeon Kim, Jamin Byun, Junshik Hong, Dong-Yeop Shin, Choong-Hyun Sun, Jaesung Kim, Ji-Joon Song, Siddhartha Jaiswal, Sung-Soo Yoon (), Sun Kim () and Youngil Koh ()
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Dohoon Lee: Seoul National University
Bonil Koo: Seoul National University
Seokhyeon Kim: Seoul National University
Jamin Byun: Seoul National University
Junshik Hong: Seoul National University
Dong-Yeop Shin: Seoul National University
Choong-Hyun Sun: Genome Opinion Inc
Jaesung Kim: Korea Advanced Institute of Science and Technology (KAIST)
Ji-Joon Song: Korea Advanced Institute of Science and Technology (KAIST)
Siddhartha Jaiswal: Stanford University
Sung-Soo Yoon: Seoul National University
Sun Kim: Seoul National University
Youngil Koh: Seoul National University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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 (DNMT3AINS) in AML, we here investigate the common characteristics of DNMT3AINS AML methylomes through computational analyses. We present that methylomes of DNMT3AINS AMLs are considerably different from those of DNMT3AR882 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.

Date: 2025
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DOI: 10.1038/s41467-024-55691-z

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