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http://hdl.handle.net/11375/28781
Title: | Using human pluripotent stem cells to discover differentiation inducers for the treatment of acute myeloid leukemia |
Authors: | Feng, Zhuohang |
Advisor: | Bhatia, Mickie Magolan, Jakob Magarvey, Nathan |
Department: | Biochemistry and Biomedical Sciences |
Publication Date: | 2023 |
Abstract: | Acute myeloid leukemia (AML) is a highly aggressive cancer that affects the hematopoietic tissue. AML exhibits a hierarchical organization; wherein leukemic stem cells (LSCs) reside at the apex of the cellular hierarchy. LSCs possess enhanced self-renewal and blocked differentiation capacity, leading to an accumulation of immature blood cells. Currently, conventional treatments for AML consist of non-selective cytotoxic chemotherapy (e.g., cytarabine), which targets rapidly dividing bulk tumour cells but fails to eliminate the LSCs. This therapeutic approach has resulted in disease relapse and poor survival in AML. In contrast, differentiation therapy, which aims to overcome the blockage of differentiation and inhibit self-renewal, has shown effective in certain malignancies. This is exemplified by the use of All-trans retinoic acid/arsenic trioxide (ATRA/ATO) treatment of acute promyelocytic leukemia (APL). Terminal differentiation induced by ATRA/ATO enables the rapid clearance of APL and leads to over 97% disease-free survival in APL patients. However, this differentiation therapy is largely limited to treating APL, which represents only 10% of AML patients. Despite extensive efforts over the decades, no other disease-drug pairing has been identified with such a clinical response. This is primarily due to the lack of understanding of differentiation pathways in heterogeneous AML disease and inadequate cell models for studying the differentiation processes of AML cells. Here, we extended the use of pluripotent stem cells (PSC) as a cell model to study the mesodermal differentiation process and apply this to AML differentiation. We hypothesize that the PSC model could facilitate the discovery of novel differentiation inducers that target multiple leukemia subtypes. To test this, we employed a range of assays, including high-content phenotypic screens (HCS), flow cytometry and colony-forming unit (CFU) assays, to identify and validate the mesoderm-specific inducers for treating AML. |
URI: | http://hdl.handle.net/11375/28781 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Feng_Zhuohang_finalsubmission202307_MSc.pdf | 2.01 MB | Adobe PDF | View/Open |
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