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

Keith Woodley; LS Dillingh; George Giotopoulos; Pedro Madrigal; KM Rattigan; Céline Philippe; Vilma Dembitz; AMS Magee; R Asby; Louie N van de Lagemaat; Christopher Mapperley; SC James; JHM Prehn; Konstantinos Tzelepis; Kevin Rouault-Pierre; George Vassiliou; Kamil Kranc; G Vignir Helgason; BJP Huntly; Paolo Gallipoli

doi:10.1038/s41467-023-37652-0

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

Keith Woodley, LS Dillingh, George Giotopoulos, Pedro Madrigal, KM Rattigan, Céline Philippe, Vilma Dembitz, AMS Magee, R Asby, Louie N van de Lagemaat, Christopher Mapperley, SC James, JHM Prehn, Konstantinos Tzelepis, Kevin Rouault-Pierre, George Vassiliou, Kamil Kranc, G Vignir Helgason, BJP Huntly, Paolo Gallipoli

Applied Medicine

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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.

Original language	English
Article number	2132
Number of pages	19
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-37652-0
Publication status	Published - 14 Apr 2023

Bibliographical note

Acknowledgements
We 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).

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. Untargeted metabolomics analysis is available in Supplemental Data 1. All data are available in the article, Supplementary Information and source data. Source data are provided with this paper.

Keywords

cancer metabolism
cancer therapeutic resistance

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Woodley, K., Dillingh, LS., Giotopoulos, G., Madrigal, P., Rattigan, KM., Philippe, C., Dembitz, V., Magee, AMS., Asby, R., van de Lagemaat, L. N., Mapperley, C., James, SC., Prehn, JHM., Tzelepis, K., Rouault-Pierre, K., Vassiliou, G., Kranc, K., Helgason, G. V., Huntly, BJP., & Gallipoli, P. (2023). Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death. Nature Communications, 14, Article 2132. https://doi.org/10.1038/s41467-023-37652-0

Woodley, K, Dillingh, LS, Giotopoulos, G, Madrigal, P, Rattigan, KM, Philippe, C, Dembitz, V, Magee, AMS, Asby, R, van de Lagemaat, LN, Mapperley, C, James, SC, Prehn, JHM, Tzelepis, K, Rouault-Pierre, K, Vassiliou, G, Kranc, K, Helgason, GV, Huntly, BJP & Gallipoli, P 2023, 'Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death.', Nature Communications, vol. 14, 2132. https://doi.org/10.1038/s41467-023-37652-0

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title = "Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death.",

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.",

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AU - Woodley, Keith

AU - Dillingh, LS

AU - Giotopoulos, George

AU - Madrigal, Pedro

AU - Rattigan, KM

AU - Philippe, Céline

AU - Dembitz, Vilma

AU - Magee, AMS

AU - Asby, R

AU - van de Lagemaat, Louie N

AU - Mapperley, Christopher

AU - James, SC

AU - Prehn, JHM

AU - Tzelepis, Konstantinos

AU - Rouault-Pierre, Kevin

AU - Vassiliou, George

AU - Kranc, Kamil

AU - Helgason, G Vignir

AU - Huntly, BJP

AU - Gallipoli, Paolo

N1 - Acknowledgements We 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).

PY - 2023/4/14

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N2 - 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.

AB - 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.

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DO - 10.1038/s41467-023-37652-0

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SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 2132

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

UN SDGs

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