Saudi Cultural Missions Theses & Dissertations
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Item Restricted Contribution of Chronic Myeloid Leukaemia Niche to Metastasis and Treatment Resistance(University of Glasgow, 2024) Albilasi, Hakem; Machesky, Laura; Kirschner, Kristina; Jorgensen, HeatherChronic myeloid leukaemia (CML) is a haematopoietic stem cell disorder hallmarked by the Philadelphia chromosome, leading to the formation of the BCR::ABL1 fusion protein and subsequent uncontrolled cell proliferation. Although the advent of tyrosine kinase inhibitors (TKIs) such as Imatinib (IM) has considerably improved patient outcomes, drug resistance and relapse remain a significant challenge. Leukaemia-related deaths and mortalities are often linked to these challenges which are a major cause of human financial and social costs of the disease. The bone marrow microenvironment (BMM) plays a crucial role in normal haematopoiesis and is also the main protection of leukaemic stem cells (LSCs). In CML, the BMM enhances leukemogenesis through an interaction with LSCs, and in turn, LSCs modify the BMM based on their requirements. Mesenchymal stem cells (MSCs) within the BMM are particularly significant, as they can support haematopoietic cells distinctly. The interactions between CML cells and the BMM, including MSCs and the extracellular matrix (ECM), have been shown to influence CML cell proliferation and responsiveness to IM. Moreover, cytoskeletal dynamics also play a crucial role in CML progression and drug resistance. In CML, alterations in cytoskeletal dynamics have been linked to drug resistance and disease progression. Therefore, this thesis will focus on the contribution BMM to these issues, with a particular interest in the role of MSCs and ECM on CML cells. In this thesis, direct contact with MSCs, treatment with MSC-conditioned media, and ECM component exposure were employed to investigate the role of the BMM and MSCs in the proliferation of CML cells and their interaction with the ECM and cell adhesion molecules. Furthermore, the effect of inhibiting specific cytoskeletal components on CML cell behaviour will be examined. The results of this thesis shed light on the complex interplay between CML cells and the BMM, highlighting the critical role of MSCs in modulating CML cell behaviour. While our results did not find a definitive impact of the ECM components on CML cell proliferation or IM sensitivity, the observations suggest that MSCs have the potential to influence the behaviour of CML cells but not definitively affecting their sensitivity to the TKI, IM. Furthermore, inhibiting cytoskeletal components such as the Arp2/3 complex and FAK did not significantly alter the CML cells' contact with MSCs. However, further investigation is necessary to investigate the molecular mechanisms regulating the interaction between CML cells and their microenvironment. Finally, the relationship between CML cells and MSCs, as shown by our transcriptomic analysis, reveals not just alterations in gene expression but also the promise of identifying novel therapeutic targets. The dysregulated pathways in co-cultured K562 cells and MSCs highlight the potential for therapeutic intervention strategies that could disrupt the supportive role of the BMM in CML persistence. The modulation of integrin alpha 9 (ITGA9) expression in K562 cells under co-culture conditions highlights the complexity of CML-MSC interaction and suggests an adaptive mechanism that may contribute to the survival and drug resistance of CML cells within the BMM. Therefore, targeting integrins could potentially enhance the efficacy of existing CML treatments, which in turn, might lead to more effective management of the disease and an increased rate of successful patient outcomes.12 0