- Title
- Single cell epigenomics in myeloid malignancies
- Creator
- Uddipto, Kumar
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are similar age progressive haematopoietic malignancies and are characterized by rapid proliferation of myeloblasts. All cancers including AML are characterized by aberrant epigenetic profiles such as altered DNA methylation. Compared to solid tumors, AML has a low mutational burden which suggests that epigenetics plays a prominent role in its development. Traditional chemotherapies in AML are often associated with severe side effects and lead to chemo-resistance in AML patients with poor cytogenetics. Hypomethylating agents (HMAs) decrease DNA demethylation, and are an alternative therapeutic option to AML and MDS patients who are greater than 65 years and cannot tolerate chemotherapy. Studies have shown that loss of global methylation after HMA treatment is not always correlated to a clinical response. Current knowledge about the molecular action of HMAs in AML is limited to the epigenetic re-expression of previously silenced genes with methylated promoters. This body of work explores the role of HMAs- Azacitidine (AZA) and Decitabine (DAC) in greater detail and shows the associations between loss of methylation and slower cell division following HMA treatment. Single cell epigenomic techniques were used for the first time in AML cells treated with HMAs, and shows heterogeneous loss of methylation between single cells. Furthermore, genes were also found to be differentially expressed as a result of treatment. Integrated multi-omics were used to link loss of DNA methylation to changes in gene expression. The results showed that loss of methylation was often negatively associated with chromatin accessibility but not gene expression. Although gene expression in certain cells are affected by DNA methylation, in other instances, gene expression is independent of DNA methylation. This study highlighted the epigenetic heterogeneity of single cells in response to HMAs and demonstrated the applicability of single cell epigenomics in cancer therapeutic studies.
- Subject
- acute myeloid leukaemia (AML); myelodysplastic syndrome (MDS); myeloblasts; myeloid malignancies
- Identifier
- http://hdl.handle.net/1959.13/1505055
- Identifier
- uon:55614
- Rights
- Copyright 2022 Kumar Uddipto
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 4 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 254 KB | Adobe Acrobat PDF | View Details Download |