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<p>The mechanistic link between the complex mutational landscape of de novo methyltransferase <i>DNMT3A</i> 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 (<i>DNMT3A</i><sup>INS</sup>) in AML, we here investigate the common characteristics of <i>DNMT3A</i><sup>INS</sup> AML methylomes through computational analyses. We present that methylomes of <i>DNMT3A</i><sup>INS</sup> AMLs are considerably different from those of <i>DNMT3A</i><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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月10日

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  • 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,
  • Youngil Koh

摘要

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.