Work

Transcriptomic changes including p53 dysregulation prime DNMT3A mutant cells for transformation

Year: 2025

Type: article

Abstract: 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 Dnmt3a R878H/+ cells. In competitive transplantations, Dnmt3a R878H/+ 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 Dnmt3a R878H/+ 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 Dnmt3a R878H/+ 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.

Source: EMBO Reports

DOI: 10.1038/s44319-025-00450-4

Authors: 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

Institutions: The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, La Trobe University, Olivia Newton-John Cancer Research Institute, Charles Sturt University, The Francis Crick Institute

Language: English

Topic: Acute Myeloid Leukemia Research

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $7,990

Funders: Wellcome Trust, Australian Rotary Health, Department of Health and Aged Care, Australian Government, National Health and Medical Research Council, Cancer Council Victoria

Awards: G1409602591, G1560280023, Regulation of Haematopoietic stem cell function by the E3 Ubiquitin ligase HectD1, Elucidating the cellular processes that are critical for p53 mediated tumour suppression, G3742123740, G5421005747, G5982373912, G6049543680, Examining the contribution of mutant DNMT3a in the development and sustained growth of Acute Myeloid Leukaemia, Understanding and exploiting how different cell death pathways control intracellular infections, G7688015494, G77499167, Using advanced CRISPR tools to improve clinical therapies for poor prognostic lymphomas, Nicotinamide Nucleotide Transhydrogenase (NNT) as a novel molecular target in the treatment of adrenocortical carcinoma., Research Fellowship

OpenAlex ID: W4409968471

FWCI: 0.654

Cites: 65

Cited by: 1

Related to: 10