Characterisation of the metabolism of AML and stromal cells in co-culture

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Vilaplana Lopera, Nuria ORCID: https://orcid.org/0000-0002-3156-9908 (2021). Characterisation of the metabolism of AML and stromal cells in co-culture. University of Birmingham. Ph.D.

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Abstract

Acute myeloid leukaemia (AML) cells are located in the bone marrow, surrounded by a complex microenvironment, known as the niche. AML cells are known to interact and modulate niche components into their own support by secreting soluble factors and cytokines. For instance, crosstalk between AML and stromal cells was reported to confer chemoresistance to AML cells. Metabolism in haematopoietic stem cells (HSCs) and AML has been broadly investigated, nonetheless, few studies have focused on understanding metabolic alterations related to the interaction between stromal and AML cells. Identifying metabolic vulnerabilities derived from these interactions can yield novel targets for the development of new therapies.
In this thesis, the metabolic changes that AML and stromal cells display in co-culture compared to single cultures have been characterised using nuclear magnetic resonance spectroscopy. An increased release of acetate into the extracellular medium was found both in AML cell lines and primary AML cells co-cultured with stromal cells, compared to cells cultured alone. Moreover, this enhanced acetate secretion did not occur when using healthy donor cells. Interestingly, increased acetate secretion was also found to be contact dependent. Transcriptomic data revealed that co-culturing AML and stromal cells resulted in a complete rewiring of stromal metabolism. Stromal cell reprogramming included increased glycolysis, accumulation of pyruvate, and decarboxylation of pyruvate to acetate mediated by reactive oxygen species. Moreover, acetate secreted by stromal cells was found to be consumed by AML cells to further use it as a carbon source to replenish the tricarboxylic acid cycle.
Overall, a unique interaction between AML and stromal cells, resulting in a reprogrammed stromal metabolism and an acetate-mediated crosstalk, is presented in this study.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):