Unravelling the roles of Slc13A3 and Slc13A5 in acute myeloid leukemia.

Details

Supervisors

van Gastel, Nick

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

enAcute myeloid leukemia (AML) is an aggressive hematopoietic malignancy characterized by the uncontrolled proliferation of undifferentiated myeloid cells. Previous work from our laboratory has shown that bone marrow stromal cells (BMSCs) further protect AML cells by stimulating their glutamine and aspartate metabolism. Interestingly BMSCs also release TCA cycle metabolites into their microenvironment. However, whether AML cells directly utilize these BMSC-derived TCA cycle metabolites remains unknown. To determine whether AML cells are capable of taking up exogenous TCA cycle metabolites, we first assessed the expression of TCA cycle metabolite transporters. We found that AML cells express both Slc13A3 and Slc13A5. We then performed a genetic knockdown of Slc13A5 in murine AML cells and exposed them to various metabolic stress conditions. Notably, Slc13A5-deficient AML cells cultured in glutamine-free media exhibited significantly increased cell death compared to control cells, suggesting that metabolites transported via Slc13A5 are critical for AML cell survival under conditions of limited glutamine availability. Additionally, Slc13A3 expression is strongly upregulated under glutamine-free conditions, suggesting increased dependence on transporter-mediated metabolite uptake. Among potential substrates, adding α-ketoglutarate restored the viability of AML cells in glutamine-free media. α- ketoglutarate can be used to generate citrate, which is then converted into cytosolic acetyl- CoA for lipid synthesis or protein acetylation. Interestingly supplementing with acetate, partially rescued the Slc13A5-deficient cells’ viability upon exposure to lower glutamine levels. This shows that the increased mortality of Slc13A5-deficient cells in glutamine-free conditions might result from a critical shortage of the acetyl-CoA pool in the cytosol. In conclusion, this project identifies Slc13A5 as a key metabolic regulator that supports AML cell survival under glutamine-deprived conditions by promoting metabolic flexibility. These findings provide new mechanistic insight into how AML cells adapt to nutrient stress and highlight Slc13A5 as a potential therapeutic target. Combining Slc13A5 inhibition with glutamine-targeted therapies may help overcome metabolic resistance and improve treatment efficacy in AML.