Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death

Keith Woodley, Laura S. Dillingh, George Giotopoulos, Pedro Madrigal, Kevin M. Rattigan, Céline Philippe, Vilma Dembitz, Aoife M. S. Magee, Ryan Asby, Louie N. van de Lagemaat, Christopher Mapperley, Sophie C. James, Jochen H. M. Prehn, Konstantinos Tzelepis, Kevin Rouault-Pierre, George S. Vassiliou, Kamil R. Kranc, G. Vignir Helgason, Brian J. P. Huntly and Paolo Gallipoli ()
Additional contact information
Keith Woodley: Queen Mary University of London
Laura S. Dillingh: University of Cambridge
George Giotopoulos: University of Cambridge
Pedro Madrigal: University of Cambridge
Kevin M. Rattigan: University of Glasgow
Céline Philippe: Queen Mary University of London
Vilma Dembitz: Queen Mary University of London
Aoife M. S. Magee: Queen Mary University of London
Ryan Asby: University of Cambridge
Louie N. van de Lagemaat: Queen Mary University of London
Christopher Mapperley: Queen Mary University of London
Sophie C. James: Queen Mary University of London
Jochen H. M. Prehn: Royal College of Surgeons in Ireland University of Medicine and Health Sciences
Konstantinos Tzelepis: University of Cambridge
Kevin Rouault-Pierre: Queen Mary University of London
George S. Vassiliou: University of Cambridge
Kamil R. Kranc: Queen Mary University of London
G. Vignir Helgason: University of Glasgow
Brian J. P. Huntly: University of Cambridge
Paolo Gallipoli: Queen Mary University of London

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37652-0

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