Burt, Richard James;
(2020)
Defining the role of mesenchymal stromal cells in treatment resistance in acute lymphoblastic leukaemia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The bone marrow microenvironment is crucial in treatment resistance in B-cell acute lymphoblastic leukaemia (B-ALL). Recent murine models suggest that treatment resistant cells are intrinsically no different to the treatment sensitive ‘bulk population’ but instead depend on a protective niche for survival. In this thesis I set out to investigate and model the mesenchymal stromal cell (MSC) niche in B-ALL. I initially showed, that MSC directly isolated from the primary bone marrow specimens of patients with B-ALL frequently adopted an activated or cancer associated fibroblast (CAF)-like phenotype. This was characterised by morphological changes, up-regulation of CAF relevant genes and enhanced cytokine/chemokine secretion. I uncovered a sub-set of B-ALL cell lines and primary B-ALL cells are capable of inducing the CAF-like phenotype in MSC cell lines and healthy donor MSC in vitro. These changes occur relative to the intrinsic reactive oxygen species (ROS) level and genetic sub-type of the B-ALL cell. Next, I showed that normal primary human MSC and the MSC cell line HS27a became activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents’ cytarabine (AraC) and daunorubicin (DNR). This phenomenon did not occur with non-ROS inducing chemotherapy - vincristine (VCR) and was blocked by NAC or the corticosteroid, dexamethasone. Finally, I demonstrated that activated MSC protected B-ALL cells from ROS-inducing chemotherapy via mitochondrial transfer through tunnelling nanotubes (TNT). Inhibition of mitochondrial transfer by selective mitochondrial depletion of MSC or interference with TNT formation by microtubule inhibitors such as VCR -prevented the ‘rescue’ function of the activated MSC. In summary, my thesis proposes a model in which the eradication of residual ALL cells by conventional chemotherapy is ineffective, at least in part due to MSC-mediated transfer of mitochondria to B-ALL cells to overcome chemotherapy induced oxidative stress at the MSC niche. My work proposes the clinically testable hypothesis that ROS inducing chemotherapies should always be combined with corticosteroids and/or microtubule inhibitors to overcome MSC mediated protection of B-ALL cells.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Defining the role of mesenchymal stromal cells in treatment resistance in acute lymphoblastic leukaemia |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10094144 |
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