Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death
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.
BCI Flow cytometry facility (CRUK Core Award C16420/A18066)
Wellcome Trust (PG, 109967/Z/15/Z)
American Society of Haematology (PG, Global Research Award)
Cancer Research UK (PG, Advanced Clinician Scientist fellowship, C57799/A27964)
Academy of Medical Sciences (SBF004\1099)
Science Foundation Ireland (SFI) under Grant Number 16/RC/3948
European Regional Development Fund
FutureNeuro industry partners
Wellcome Trust (Grant References: RG94424, RG83195, G106133)
UKRI Medical Research Council (RG83195)
Leukaemia UK (G108148)
Associated research data filesThe RNA-sequencing data generated in this study have been deposited in the ArrayExpress database and are available at https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-11750.
CommentsThe original article is available at https://www.nature.com/
Published CitationWoodley K, et al. Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death. Nat Commun. 2023;14(1):2132.
Publication Date14 April 2023
- Physiology and Medical Physics
PublisherSpringer Nature Limited
- Published Version (Version of Record)