Nature communications · 2023
Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death.
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Woodley Keith, Dillingh Laura S, Giotopoulos George, Madrigal Pedro, Rattigan Kevin M, Philippe Céline, Dembitz Vilma, Magee Aoife M S, Asby Ryan, van de Lagemaat Louie N, Mapperley Christopher, James Sophie C, Prehn Jochen H M, Tzelepis Konstantinos, Rouault-Pierre Kevin, Vassiliou George S, Kranc Kamil R, Helgason G Vignir, Huntly Brian J P, Gallipoli Paolo
Аннотация
Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.