Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death Article Swipe
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
,
Paolo Gallipoli
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1101/2022.05.16.492042
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1101/2022.05.16.492042
Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukemia (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 novel 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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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2022.05.16.492042
- https://www.biorxiv.org/content/biorxiv/early/2022/05/16/2022.05.16.492042.full.pdf
- OA Status
- green
- References
- 67
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4280586493
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4280586493Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1101/2022.05.16.492042Digital Object Identifier
- Title
-
Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell deathWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2022Year of publication
- Publication date
-
2022-05-16Full publication date if available
- Authors
-
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, Paolo GallipoliList of authors in order
- Landing page
-
https://doi.org/10.1101/2022.05.16.492042Publisher landing page
- PDF URL
-
https://www.biorxiv.org/content/biorxiv/early/2022/05/16/2022.05.16.492042.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.biorxiv.org/content/biorxiv/early/2022/05/16/2022.05.16.492042.full.pdfDirect OA link when available
- Concepts
-
Myeloid leukemia, Cytarabine, Cancer research, Metabolism, Programmed cell death, Mannose, Leukemia, Metabolic pathway, Chemistry, Biochemistry, Biology, Apoptosis, ImmunologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- References (count)
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67Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W3080935763, https://openalex.org/W1984209370, https://openalex.org/W2810336146, https://openalex.org/W3167360675, https://openalex.org/W2162520885, https://openalex.org/W2980245695, https://openalex.org/W3094799743, https://openalex.org/W3119878501, https://openalex.org/W2803962537, https://openalex.org/W2047122678, https://openalex.org/W2088253442, https://openalex.org/W2768054923, https://openalex.org/W2605757478, https://openalex.org/W1984000875, https://openalex.org/W2137596099, https://openalex.org/W2036810334, https://openalex.org/W2005455329, https://openalex.org/W2033923444, https://openalex.org/W1970122244, https://openalex.org/W2128606509, https://openalex.org/W2662007953, https://openalex.org/W2041574453, https://openalex.org/W2901320017, https://openalex.org/W3158744925, https://openalex.org/W2892247627, https://openalex.org/W2131862463, https://openalex.org/W2898648224, https://openalex.org/W2023418900, https://openalex.org/W1986353798, https://openalex.org/W1599923603, https://openalex.org/W2168768454, https://openalex.org/W2754464449, https://openalex.org/W2061774676, https://openalex.org/W2259320992, https://openalex.org/W2483976919, https://openalex.org/W2495220859, https://openalex.org/W2476887811, https://openalex.org/W2071273959, https://openalex.org/W1970090817, https://openalex.org/W2019192392, https://openalex.org/W2909588203, https://openalex.org/W2806219344, https://openalex.org/W2932111434, https://openalex.org/W2149212516, https://openalex.org/W2024519961, https://openalex.org/W2163294546, https://openalex.org/W2592029987, https://openalex.org/W3201050288, https://openalex.org/W1964005583, https://openalex.org/W3029351535, https://openalex.org/W3111904808, https://openalex.org/W2736569880, https://openalex.org/W1950465699, https://openalex.org/W2050457036, https://openalex.org/W3136017577, https://openalex.org/W3095977572, https://openalex.org/W3213657507, https://openalex.org/W3176312941, https://openalex.org/W1997183854, https://openalex.org/W2762087180, https://openalex.org/W2767055857, https://openalex.org/W4313251792, https://openalex.org/W3134959125, https://openalex.org/W3167697154, https://openalex.org/W3157598024, https://openalex.org/W1930708124, https://openalex.org/W3099912018 |
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| abstract_inverted_index.we | 30, 59 |
| abstract_inverted_index.AML | 56, 104, 118, 140 |
| abstract_inverted_index.Our | 106 |
| abstract_inverted_index.and | 4, 18, 51, 66, 99, 131 |
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| abstract_inverted_index.arm | 79 |
| abstract_inverted_index.the | 8, 37, 41, 77, 81, 112 |
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| abstract_inverted_index.ATF6 | 78 |
| abstract_inverted_index.FLT3 | 52 |
| abstract_inverted_index.Here | 29 |
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| abstract_inverted_index.death. | 148 |
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| cited_by_percentile_year | |
| corresponding_author_ids | https://openalex.org/A5018919552 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 20 |
| corresponding_institution_ids | https://openalex.org/I166337079 |
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| sustainable_development_goals[0].display_name | Good health and well-being |
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| citation_normalized_percentile.is_in_top_10_percent | False |