Protein S-acylation dynamics provide metabolic flexibility to acute myeloid leukemia cells
(2025) European Hematology Association 2025 Congress, Molecular Hematopoiesis Workshop — Location: Milan, Italy (12.June.2025)
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- Abstract
- While cancer cells have been identified to have a metabolism distinct from normal cells for almost a century, the clinical success of targeting metabolic enzymes for cancer therapy remains limited. A key reason for this is the ability of cells to rewire their metabolism and adapt to the blockage of a single pathway. Here, we use acute myeloid leukemia (AML), a highly lethal blood cancer, as a model to investigate metabolic flexibility by treating human AML cell lines with random combinations of metabolic inhibitors. A synthetic lethality was observed when AML cells were simultaneously exposed to glutaminase inhibitors and TOFA, a hypolipidemic agent. Sensitivity to this metabolic inhibitor combination was equally seen in primary AML patient samples, including in leukemic stem cells, but healthy hematopoietic stem and progenitor cells (HSPCs) were not affected. Unexpectedly, we discovered that TOFA exerts its cytotoxic effects through a non-canonical inhibition of protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 16-to-18 carbon long fatty acids and is essential to maintain correct mitochondrial function. Upon inhibition of glutaminolysis, a shift in S-acylation towards glycolytic enzymes allows metabolic adaptation and assures leukemic cell survival. In contrast to AML cells, healthy HSPCs have a much higher intrinsic metabolic flexibility that is independent of metabolic enzyme S-acylation. Taken together, our results identify a new mechanism of metabolic flexibility in AML that may be exploited to potentiate metabolic anti-cancer drugs such as glutaminase inhibitors.
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van Gastel, N., & et al. (2025). Protein S-acylation dynamics provide metabolic flexibility to acute myeloid leukemia cells. European Hematology Association 2025 Congress, Molecular Hematopoiesis Workshop, Milan, Italy. https://hdl.handle.net/2078.5/247471