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Imbalance of DNA methylation and demethylation as pathogenic mechanism of acute leukaemia

Mehmetbeyoglu Duman, Sevim 2023. Imbalance of DNA methylation and demethylation as pathogenic mechanism of acute leukaemia. PhD Thesis, Cardiff University.
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Acute myeloid leukaemia (AML) is driven by acquired genetic changes, somatic driver mutations caused by chromosomal alterations for instance translocations or point mutations. About 60% of AMLs present chromosomal translocations. These translocations result in the formation of fusion genes encoding chimeric transcription factors. AML with normal karyotype is attributed to specific somatic point mutations. Notably, some of these mutations follow a specific chronological order. For example DNMT3A, IDH1 or IDH2, and NPM1 alterations occur in sequence. This group of nonrandom point mutations and translocations have a functional connection, as all impact the balance between DNA methylation and demethylation. The intermediates of oxidative demethylation represent DNA damage signals that have the potential to increase mutagenesis if not repaired. Our study aimed to elucidate the role of specific mutations and their combinations in shaping the leukaemia phenotype, which is characterised by increased self-renewal and differentiation block of leukaemia blasts. Additionally, we investigated the role of DNA damage and repair (DDR) in this context. We also explored the role of aberrant methylation/demethylation in leukemogenesis. Therefore, we expressed various constructs in murine Sca-1 + /linhaematopoietic progenitor and stem cells. These included DNMT3A, DNMT3AR882H, DNMT3A-IDH2, DNMT3AR882H-IDH2R140Q, DNMT3A-IDH2-NPM1, and DNMT3AR882HIDH2R140Q-NPM1mutA, alongside control constructs, like PML::RARα. We assessed methylation (5'mC) and demethylation (5'hmC, 5'fC) rates and investigated the differentiation via surface marker expression. Our analysis aimed to identify the role of these mutations and their impact on DDR pathways. We sought insights into affected DDR mechanisms and how these mutations contribute to leukemogenesis. Somatic mutations and translocations intricately interact in leukemogenesis, driving abnormal stem cell activity while inhibiting differentiation. Dysregulated methylation, induced by chromosomal translocations such as PML::RARα, DEK::CAN, BCR::ABL1 and somatic point mutations such as expression of mutated DNMT3AR882H alone or with IDH2R140Q and NPM1mutA, disrupts DDR mechanisms. We found evidence that DNMT3AR882H impairs DNA mismatch repair. Our study sheds light on the complex interplay of epigenetic dysregulation and DDR in AML, providing insights for potential therapeutic interventions.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 14 March 2024
Last Modified: 14 Mar 2024 14:29

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