Investigating the role of the Dnmt3a R882H mutation in subverting normal haematopoiesis and in malignant transformation (360G-Wellcome-337992_Z_25_Z)

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.