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Characterisation of extracellular vesicles from the microenvironment in high risk acute myeloid leukaemia

Lazenby, Michelle 2019. Characterisation of extracellular vesicles from the microenvironment in high risk acute myeloid leukaemia. MPhil Thesis, Cardiff University.
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Abstract

Haematopoietic stem cell transplantation is the most effective anti-leukaemic therapy for AML for a large number of patients, but a significant proportion of these will relapse post-transplant with a poor prognosis for long-term survival. The bone marrow microenvironment has been implicated as a major contributor to chemotherapy resistance and relapse through mediating communications between residual cells which have been shown to preferentially support and maintain the leukaemic niche. Interactions within this malignant niche can be facilitated by exosomes, extracellular vesicles secreted by multiple cell types that function as delivery vehicles for mRNA, DNA, miRNA, enzymes and cytokines. The ability of secreted exosomes to induce microenvironmental changes that may differentially support normal or malignant stem cells in the post-transplant setting is relatively unknown. Characterisation of exosomes originating from MSCs revealed exosome particle number and protein content was significantly increased in diagnostic MSC samples compared to normal and post-BMT samples, along with miRNA yield which was also found to be significantly higher in this patient sub-set. Ex vivo co-culture assays using functional exosome preparations from primary AMLMSCs revealed several phenotypic effects including exosome induced proliferation when co-cultured with primary AML blasts, cell adhesion and a significant protection against drug treatment. Secreted cytokine profiling by Luminex bead capture array showed that exosome cytokine profile change from adhesion related within the NBM and diagnostic samples, to immunology related targets in early-BMT and adhesion and survival/differentiation related in late-BMT. This change reflects a stabilization of the inflammatory environment towards NBM levels, along with an increase in adhesion related molecules suggesting a recovery post-transplant and potential early indication of disease relapse, GvHD or GvL. These results demonstrate how important extracellular vesicles are in creating a hostile microenvironment as promotors of residual disease, and for the first time the malignant potential of microenvironment derived MSC exosomes in AML.

Item Type: Thesis (MPhil)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 4 February 2020
Last Modified: 04 Feb 2020 09:52
URI: http://orca-mwe.cf.ac.uk/id/eprint/129278

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