Royal College of Surgeons in Ireland
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Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death

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posted on 2023-04-27, 15:45 authored by 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 PrehnJochen Prehn, Konstantinos Tzelepis, Kevin Rouault-Pierre, George S Vassiliou, Kamil R Kranc, G Vignir Helgason, Brian J P Huntly, Paolo Gallipoli

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. 

Funding

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)

History

Data Availability Statement

The 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.

Comments

The original article is available at https://www.nature.com/

Published Citation

Woodley 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 Date

14 April 2023

PubMed ID

37059720

Department/Unit

  • Physiology and Medical Physics

Publisher

Springer Nature Limited

Version

  • Published Version (Version of Record)