Analysis of the transcriptome for novel therapeutic targets, and investigation of the role of APOBEC3B in chronic myeloid leukaemia stem cells

Jackson, Lorna (2018) Analysis of the transcriptome for novel therapeutic targets, and investigation of the role of APOBEC3B in chronic myeloid leukaemia stem cells. PhD thesis, University of Glasgow.

Abstract

The introduction to the clinic of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukaemia (CML) revolutionized the outlook for patients. These drugs manage disease highly effectively in the majority of patients, through elimination of the bulk of the leukaemic cells from the blood and bone marrow. However, they fail to eradicate the underlying leukaemic stem cells (LSCs). Therefore, patients are not cured, and the prevalence of CML is rising year-by-year. As LSCs display increased genomic instability, their persistence risks the evolution of TKI-resistant clones. In order to eliminate these cells and cure CML, novel therapeutic strategies are required. As LSCs do not depend on the activity of breakpoint cluster region/abelson murine leukaemia viral oncogene homolog 1 (BCR-ABL1), the causative oncogene underlying CML biology for their survival, the key to eradicating these TKI-persistent cells may lie in the targeting of other pathways important for their survival and maintenance. Here, an in silico approach was employed for the detection of differences between CML and normal stem cells that may allow selective targeting of survival, maintenance and evolution in LSCs.
A growing collection of high-quality publicly available datasets describing genomic-scale gene expression in CML cells represents a valuable resource for the identification of novel targets. Though genome-scale data allow us to explore CML biology on a systems-level, the datasets themselves often have small sample numbers and high variability, and therefore reduced statistical power for the robust detection of differences between sample types. A meta-analysis assessing CML versus normal gene expression in five datasets from the TKI-refractory stem/quiescent cell fractions was performed to identify robustly differentially expressed (DE) genes. In addition to protein coding genes, microRNAs (miRNAs) are emerging as critical regulators of many aspects of cancer biology. Genome-scale miRNA expression datasets were additionally analysed to identify the potential roles of miRNAs in LSC biology. Following these computational analyses, the nucleic acid editor apolipoprotein B mRNA editing catalytic polypeptide-like 3B (APOBEC3B) was investigated for evidence of involvement in CML biology in its capacity as a driver of mutation and subsequent evolution, and in other aspects of CML cell function.
The experiments described here reveal genome-scale transcriptomic differences between LSCs and HSCs, with potentially important functional implications. The results contribute towards building a more holistic view of the biological state of LSCs on a systems level.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Funder's Name: Medical Research Council (MRC)
• Supervisor's Name: Jorgensen, Dr. Heather, Rogers, Dr. Simon, Hopcroft, Dr. Lisa and Holyoake, Prof. Tessa
• Date of Award: 2018
• Embargo Date: 24 September 2022
• Depositing User: Mrs Marie Cairney
• Unique ID: glathesis:2018-75031
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 24 Sep 2019 11:52
• Last Modified: 11 Aug 2022 10:04
• Thesis DOI: 10.5525/gla.thesis.75031
• URI: https://theses.gla.ac.uk/id/eprint/75031

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