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http://hdl.handle.net/11375/18675
Title: | Interactive properties of leukemia stem cells with their environment |
Authors: | Boyd, Allison L |
Advisor: | Bhatia, Mickie |
Department: | Biochemistry and Biomedical Sciences |
Publication Date: | 2016 |
Abstract: | Rare cancer stem cells are thought to be responsible for relapsed disease in many malignancies due to their preferential ability to evade cytotoxic therapy. The hierarchical organization of cancer has been most thoroughly described in acute myeloid leukemia (AML), in which leukemia stem cells (LSCs) have been shown to both self-renew, and generate short-lived dysfunctional progeny. To date, most investigational efforts to eradicate these cells have focused on their intrinsic attributes. However, stem cell identities in the normal hematopoietic system are uniquely maintained through associations with the microenvironment. Similar context-dependent behaviour may also apply to malignant stem cells, although this has not been well explored in AML. Therefore, I hypothesized that AML-LSCs are sensitive to the conditions of their external environment, and that these influences can be used to both understand chemotherapy resistance mechanisms, and to devise novel therapeutic strategies. We began by providing evidence that LSCs cannot be distinguished from healthy hematopoietic stem cells (HSCs) based on a signaling pathway that has been clinically shown to have therapeutic promise in AML. Instead, we showed that non-hematopoietic cells in the bone marrow (BM) are more sensitive to these signals, which may impact neighbouring LSCs in a non-cell-autonomous manner. We then investigated whether LSCs interact with abnormal “niches” in BM, using sophisticated xenograft modeling. Based on in situ tissue analysis and in vivo functional assays, we found that LSCs directly compete with healthy HSCs for shared niche occupancy in BM, and equally require niche support to sustain their self-renewal. Furthermore, this dependence could be exploited by cytokine dissociation of LSC-niche interactions during transplantation therapy, to promote competitive replacement by healthy HSCs. Finally, we investigated the in vivo cellular events that lead to leukemic relapse after chemotherapy, a process thought to occur due to niche-mediated protection of quiescent LSCs. Our findings however challenge the conventional view that LSCs are preferentially spared by cytotoxic therapy. While primitive leukemic cells are initially suppressed following chemotherapy, we show that a unique population assembles to regenerate the disease at a rate disproportionate to healthy recovery. Focusing on these cells, we have described novel molecular hallmarks of leukemic regeneration, and demonstrated that they can be targeted in combination with chemotherapy to durably suppress leukemic growth. Collectively, the data presented within this thesis offer a broader conceptualization of LSCs as interactive components of the BM environment. This has revealed novel therapeutic paths to ultimately enable LSC targeting on multiple fronts. |
URI: | http://hdl.handle.net/11375/18675 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Allison Boyd PhD Thesis 2015.pdf | Allison Boyd PhD thesis 2015 | 40.27 MB | Adobe PDF | View/Open |
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