Active Genetics & Molecular Biology Cancer

Investigating the role of the Dnmt3a R882H mutation in subverting normal haematopoiesis and in malignant transformation

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

A single letter change in a DNA-modifying enzyme—swapping one amino acid for another at position 882—drives a tenth of all acute myeloid leukaemia cases and is the most common mutation found in pre-cancerous blood cells. This matters because doctors currently have no way to stop that mutation from pushing healthy blood stem cells toward leukaemia. The mutation disables the enzyme’s normal job of adding chemical tags to DNA, but the research team suspects it also does something else entirely: it may hijack the enzyme’s ability to directly switch genes on and off, independent of those chemical tags. If confirmed, that would explain why current drugs targeting the tagging mechanism fail in these patients. The project will map this hidden gene-control function, test whether it disrupts a key tumour-suppressor pathway involving TP53, and then screen for drugs that block the rogue activity. Success would identify the first targeted treatments for the roughly 20% of AML patients carrying this mutation—people who today have no therapy tailored to their cancer’s specific driver.

View original technical description
The DNMT3A R882H mutation is a highly recurrent driver of Clonal Haematopoiesis (CH) and is further linked to leukaemic transformation, being recurrently present in chronic myeloid malignancies such as Myelodysplastic syndromes (MDS), Myeloproliferative Neoplasms (MPN), as well as in up to 20% of Acute Myeloid Leukaemia (AML) cases. Mutations in DNMT3A have been shown to result in global DNA hypomethylation, but the causal link between these epigenetic changes and gene expression alterations, as well as to progression from normal haematopoiesis to AML, remains unclear. Emerging evidence suggests that mutations in DNMT3A could also affect its non-catalytic, transcription factor (TF)-like functions, and affect gene regulation independently of its methyltransferase activity. This project aims to investigate the mechanism(s) by which DNMT3A R882H promotes malignant transformation, focusing on its non- catalytic functions. Specifically, I will: 1. Investigate the DNA methylation- independent functions of DNMT3A R882H in normal and malignant haematopoiesis. 2. Dissect the DNMT3A–TP53 pathway interplay, a possible promising downstream mechanism raised by preliminary findings in the Huntly lab. 3. Identify and test therapeutic vulnerabilities across the CH–AML continuum, using key findings from Aims 1 and 2.

View the original record at the funder ↗

Researchers

Juri Yo (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Development and characterisation of a DNMT3A mutant cell line model of clonal haematopoiesis
Preventing and Understanding CHIP Evolution into AML: The role of the LY75 in the development of DNMT3A-mutant CH and associated myeloid neoplasms
Deciphering the role of germline variants in the RNA-helicases to improve the early detection and management of familial MDS/AML patients
Deciphering the mechanisms of epigenetic evolution driving leukaemia
Targeting of aberrant epigenetic circuitries and associated DNA damage response in acute myeloid leukaemia

Original classification

PhD Studentship (Basic)

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