James, AllanAlharbi, Abrar Abdulghani2024-09-112024-09-112024-02https://hdl.handle.net/20.500.14154/73057Acute Myeloid Leukaemia (AML) is a group of highly heterogeneous haematological malignancies that arises from the accumulation of acquired genetic lesions, including point mutations, translocations, and DNA copy number alterations (CNAs) that confer a survival advantage to the leukaemic cell. The identification and characterisation of these aberrations have not only shed light on the pathogenesis of AML but also have improved patient stratification and the selection of therapeutic strategies. Despite these advances, drug resistance and relapse remain persistent clinical challenges, which may reflect the presence of as yet undetected alterations that influence disease progression and outcome. Recent advances in high throughput platforms such as microarray‐based genotyping technologies have revealed previously unrecognised cryptic chromosomal aberrations associated with DNA copy number changes. Given the heterogeneity of AML genomes, input from these platforms can potentially supplement cytogenetic data to improve prognostication and guide treatment decisions, and perhaps lend further insight into the mechanisms underlying AML pathogenesis. In this study, we analysed SNP‐microarray data from a large cohort of over 3000 AML cases for CNAs and copy‐neutral regions of homozygosity. In addition to providing a comprehensive overview of the landscape of acquired CNAs and regions of homozygosity in AML, this large cohort enabled us to identify and validate recurrent novel focal CNAs. Among validated gene targets affected by focal CNA is MIR4447, a previously uncharacterised microRNA. To investigate the potential role of MIR4447 in AML pathogenesis, we developed both gain‐ and loss‐of‐function cell models via gene overexpression and CRISPR/cas9‐mediated gene editing, respectively. These models were interrogated using RNA sequencing to analyse the transcriptional impact of miR‐4447 modulation. Our findings suggest that miR‐4447 has a multifaceted and context‐dependant role in regulating cellular functions, impacting energy metabolism, ribosome synthesis, immune response, and possibly leukaemogenesis through alterations in nutrient transport, mitochondrial function, and cell migration. Collectively, our findings contribute to our understanding of the genomic intricacies of AML and highlight the need for further research to investigate the downstream targets of miR‐4447, its effects in different cellular contexts, and its interaction with other regulatory molecules.357enAMLCancerCNAsMIR4447MicroRNAThesis