Acute myeloid leukemia (AML) is an aggressive cancer of the blood and bone marrow, affecting 1,100 Canadians annually. Older patients make up 75% of cases yet have the lowest survival rates due to the lack of tolerable treatments. Recently, the combination of Venetoclax and Azacitidine (Ven/Aza) has shown great therapeutic promise, however, chemoresistance has become a growing concern. Current evidence points towards a chemoprotective role from the bone marrow (BM) microenvironment, specifically by BM-derived mesenchymal stromal cells (BMSCs) and adipocytes. AML cells can manipulate BMSCs and adipocytes to create a niche that supports its own growth and evades chemotherapy. However, the role of the microenvironment in Ven/Aza chemoresistance has yet to be studied. Our objective was to study the ability of the microenvironment cells to induce AML chemoresistance to Ven/Aza. We employed a 2-dimensional direct contact co-culture system between MOLM-13 AML cells and BMSCs or adipocytes in both the absence and presence of Ven/Aza to determine the effects on the AML cells. In the absence of Ven/Aza, adipocyte co-cultured AML cells showed a 47% reduction in proliferation, 10% reduction in viability, yet a 1.7-fold increase in Maximal respiration when compared to the monocultured cells. In the presence of Ven/Aza, adipocyte co-cultured AML cells showed a significant increase in both proliferation and viability. Preliminary work investigating the mechanism of action of this support points toward an anti-apoptotic mechanism mediated by the upregulation of MCL-1 upon co-culture with adipocytes. Combination of Venetoclax and Tapotoclax, an MCL-1 inhibitor, abrogated the chemoprotection provided by BMSCs and adipocytes. Overall, our data suggests a dual role of adipocytes, where their inhibition or support of AML is context dependent. Therapeutic targeting of mechanisms for adipocyte chemoprotection such as MCL-1 upregulation may re-sensitize AML cells to Ven/Aza, thereby improving patient outcomes. / Thesis / Master of Science (MSc) / Acute myeloid leukemia (AML) is an aggressive cancer of the blood and bone marrow, affecting 1,100 Canadians annually. Older patients make up 75% of cases yet have the lowest survival rates due to the lack of tolerable treatments. A novel combination of Venetoclax and Azacitidine (Ven/Aza) has shown great therapeutic promise, however, chemoresistance remains an important concern. Previous studies have implicated fat cells, or adipocytes, in AML chemoresistance, however, their role in Ven/Aza treatment has yet to be studied. Here, we show that adipocytes reduce growth of AML cells, yet enhance their metabolism. In the presence of Ven/Aza, adipocytes induce chemoresistance. We show preliminary data that this chemoprotection may be mediated by the upregulation of mitochondrial MCL-1 protein as inhibition of this protein neutralized the protection. By understanding the relationship between adipocytes and AML chemoresistance, we can target this and re-sensitize AML to Ven/Aza, thereby improving older patient outcomes.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27966 |
| Date | 11 1900 |
| Creators | Prabagaran, Pradhariny |
| Contributors | Berg, Tobias, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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