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<p><i>DNMT3A</i> mutations are prevalent in haematologic malignancies. In our mouse model the murine homologue (R878H) of the human ‘hotspot’ R882H mutation is introduced into the mouse <i>Dnmt3a</i> locus. This results in globally reduced DNA methylation in all tissues. Mice with heterozygous R878H <i>DNMT3A</i> mutations develop γ-radiation induced thymic lymphoma more rapidly than control mice, suggesting a vulnerability to stress stimuli in <i>Dnmt3a</i><sup><i>R878H/+</i></sup> cells. In competitive transplantations, <i>Dnmt3a</i><sup><i>R878H/+</i></sup> Lin<sup>-</sup>Sca-1<sup>+</sup>Kit<sup>+</sup> (LSK) haematopoietic stem/progenitor cells (HSPCs) have a competitive advantage over WT HSPCs, indicating a self-renewal phenotype at the expense of differentiation. RNA sequencing of <i>Dnmt3a</i><sup><i>R878H/+</i></sup> LSKs exposed to low dose γ-radiation shows downregulation of the p53 pathway compared to γ-irradiated WT LSKs. Accordingly, reduced PUMA expression is observed by flow cytometry in the bone marrow of γ-irradiated <i>Dnmt3a</i><sup><i>R878H/+</i></sup> mice due to impaired p53 signalling. These findings provide new insights into how <i>DNMT3A</i> mutations cause subtle changes in the transcriptome of LSK cells which contribute to their increased self-renewal and propensity for malignant transformation.</p>

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Transcriptomic changes including p53 dysregulation prime DNMT3A mutant cells for transformation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月30日

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  • Erin M Lawrence,
  • Amali Cooray,
  • Andrew J Kueh,
  • Martin Pal,
  • Lin Tai,
  • Alexandra L Garnham,
  • Connie S N Li-Wai-Suen,
  • Hannah Vanyai,
  • Quentin Gouil,
  • James Lancaster,
  • Sylvie Callegari,
  • Lauren Whelan,
  • Elizabeth Lieschke,
  • Annabella Thomas,
  • Andreas Strasser,
  • Yang Liao,
  • Wei Shi,
  • Andrew H Wei,
  • Marco J Herold

摘要

DNMT3A mutations are prevalent in haematologic malignancies. In our mouse model the murine homologue (R878H) of the human ‘hotspot’ R882H mutation is introduced into the mouse Dnmt3a locus. This results in globally reduced DNA methylation in all tissues. Mice with heterozygous R878H DNMT3A mutations develop γ-radiation induced thymic lymphoma more rapidly than control mice, suggesting a vulnerability to stress stimuli in Dnmt3aR878H/+ cells. In competitive transplantations, Dnmt3aR878H/+ Lin-Sca-1+Kit+ (LSK) haematopoietic stem/progenitor cells (HSPCs) have a competitive advantage over WT HSPCs, indicating a self-renewal phenotype at the expense of differentiation. RNA sequencing of Dnmt3aR878H/+ LSKs exposed to low dose γ-radiation shows downregulation of the p53 pathway compared to γ-irradiated WT LSKs. Accordingly, reduced PUMA expression is observed by flow cytometry in the bone marrow of γ-irradiated Dnmt3aR878H/+ mice due to impaired p53 signalling. These findings provide new insights into how DNMT3A mutations cause subtle changes in the transcriptome of LSK cells which contribute to their increased self-renewal and propensity for malignant transformation.