EXPLOITING GLUTAMINOLYSIS AS A THERAPEUTIC TARGET IN NON-HODGKIN LYMPHOMA
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Tumours rewire their metabolism to meet the increased biosynthetic and energetic demands of proliferation. Many are critically reliant on glutamine metabolism, which offers an underutilised therapeutic opportunity. The Myc oncogene drives metabolic reprogramming to promote glutamine addiction, is commonly aberrantly expressed in Non-Hodgkin lymphoma, and is associated with an aggressive clinical course. Therefore, glutaminolysis inhibition could provide a powerful therapeutic strategy for these tumours. However, tumours are highly plastic and respond to metabolic inhibitors by incorporating different nutrient sources and calling on alternative metabolic pathways to sustain their survival and proliferation. Combined targeting of glutaminolysis with specific compensatory metabolic pathways could therefore yield synergistic effects. However, metabolic profiles both between and within lymphoma subtypes are diverse, and they employ different strategies to compensate for glutaminolysis inhibition. A greater understanding of their nuanced responses should reveal individual, specific therapeutic targets. Additionally, despite the avid consumption of glutamine upon activation of healthy, naïve B-Cells, its metabolic fate and the functions that it supports have been under investigated. Here I demonstrate that Myc overexpression in Diffuse Large B-Cell Lymphoma elicits increased expression of mitochondrial metabolism genes and of the gene encoding glutaminase, the rate limiting step in glutamine metabolism. Glutaminase inhibition led to varied responses in B-Cell lymphomas, revealing several potential mechanisms through which glutaminase inhibition is evaded. Tracing studies using 13C labelled glutamine in a treatment resistant cell line revealed that it was used as an anaplerotic fuel and converted to aspartate, in addition to being used for oxidative phosphorylation. Finally, I show that glutaminolysis enzymes are specifically expressed in germinal centres in human lymphoid tissue and that growth following activation of naïve B-cells is critically reliant on glutamine, both downstream and independently of glutaminase.
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Joseph, NCollections
- Theses [4235]