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dc.contributor.advisorSzegezdi, Eva
dc.contributor.authorO' Reilly, Eimear
dc.date.accessioned2020-06-15T08:51:14Z
dc.date.issued2020-06-12
dc.identifier.urihttp://hdl.handle.net/10379/16017
dc.description.abstractAcute myeloid leukaemia (AML) is a heterogenous clonal disorder characterised by the accumulation of immature, non-functional and highly proliferative blasts in the bone marrow and periphery. AML has a high relapse rate, and even in patients who achieve complete remission after treatment, 30-40% will eventually relapse. It is well known that a sub-population of quiescent leukemic stem cells (LSCs) are responsible for patient relapse. The bone marrow microenvironment (BMM) and its interaction with leukemic cells is becoming increasingly recognised for its role in driving drug resistance and patient relapse in AML. Two primary mechanisms of BMM-mediated drug resistance are discussed in this thesis, namely quiescence-driven drug resistance and the upregulation of anti-apoptotic proteins in AML cells. We have developed a non-contact, layered co-culture system that can faithfully replicate the quiescent-AML BMM. Utilising bone marrow mesenchymal stem cells (BMSCs), transforming growth factor beta-1 (TGFβ-1) and conditions of hypoxia, we were able to induce a quiescent-like state in the AML cell line, KG1a cells. This quiescent model was found to be suitable for long-term culture and readily transferable to co-axial beads. With these beads, high throughput screening was conducted and potential candidate treatments for the reactivation of AML cells from their protective, quiescent state were identified. This is a powerful tool to identify potential novel treatment combinations for the eradication of LSCs and thus, prevent patient relapse. By employing a second model, a direct-contact co-culture system of BMSCs and AML cells, the role of the BMM in protecting AML cells from cytotoxic agents was studied. It was discovered that BMSCs drive the expression of the anti-apoptotic Bcl-2 protein family in AML cells, and that Mcl-1 expression was induced over both Bcl-2 and Bcl-XL. Inhibition or repression of Mcl-1 was able to revert the protective effect exerted by the BMM on AML cells and primary blasts. Notably, the CD34+/CD38- LSC representative cells were re-sensitised to cytarabine+daunorubicin. This highlights the potential therapeutic targeting of Mcl-1 to revert BMM-mediated drug resistance.en_IE
dc.publisherNUI Galway
dc.subjectAcute myeloid leukaemiaen_IE
dc.subjectBone marrow microenvironmenten_IE
dc.subjectBcl-2 proteinsen_IE
dc.subjectQuiescenceen_IE
dc.subjectCanceren_IE
dc.subjectDrug resistanceen_IE
dc.subjectAMLen_IE
dc.subjectNatural Scienceen_IE
dc.subjectBiochemistryen_IE
dc.titleMechanisms of bone marrow-mediated drug resistance in acute myeloid leukaemiaen_IE
dc.typeThesisen
dc.contributor.funderIrish Research Councilen_IE
dc.contributor.funderThomas Crawford Hayes Research Awarden_IE
dc.local.noteAcute myeloid leukaemia (AML) is an aggressive cancer of the blood and bone marrow with a high relapse rate even after successful chemotherapy. It is now well known that relapse is due to the presence of leukemic stem cells (LSC). LSCs can reside in pockets in the bone marrow, where they are protected from chemotherapeutics. This thesis will describe two mechanism of bone marrow-driven drug resistance in AML and how these can be targeted to prevent disease relapse.en_IE
dc.description.embargo2024-06-12
dc.local.finalYesen_IE
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