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

Woodley, K. et al. (2023) Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death. Nature Communications, 14, 2132. (doi: 10.1038/s41467-023-37652-0) (PMID:37059720) (PMCID:PMC10104861)

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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.

Item Type:Articles
Additional Information:The authors wish to thank the Barts Cancer Institute tissue bank for sample collection and processing. This research was supported by the BCI Flow cytometry facility (CRUK Core Award C16420/A18066). This work was supported by the Wellcome Trust (PG, 109967/Z/15/Z), the American Society of Haematology (PG, Global Research Award) and Cancer Research UK (PG, Advanced Clinician Scientist fellowship, C57799/A27964). K.R-P. was supported by the Academy of Medical Sciences (SBF004\1099) J.H.M.P. was supported by a research grant from Science Foundation Ireland (SFI) under Grant Number 16/RC/3948 and co-funded under the European Regional Development Fund and by FutureNeuro industry partners. K.T. was funded by Wellcome Trust (Grant References: RG94424, RG83195, G106133), UKRI Medical Research Council (RG83195) and Leukaemia UK (G108148).
Glasgow Author(s) Enlighten ID:Rattigan, Dr Kevin and Helgason, Professor Vignir
Authors: Woodley, K., Dillingh, L. S., Giotopoulos, G., Madrigal, P., Rattigan, K. M., Philippe, C., Dembitz, V., Magee, A. M. S., Asby, R., van de Lagemaat, L. N., Mapperley, C., James, S. C., Prehn, J. H. M., Tzelepis, K., Rouault-Pierre, K., Vassiliou, G. S., Kranc, K. R., Helgason, G. V., Huntly, B. J. P., and Gallipoli, P.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Nature Communications
Publisher:Nature Research
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Nature Communications 14: 2132
Publisher Policy:Reproduced under a Creative Commons License

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