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 mannos...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37652-0 |
| _version_ | 1797845891640459264 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Keith Woodley |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:46:19Z |
| format | Article |
| id | doaj.art-a02c0de22e004847b729037f65f8b163 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T17:46:19Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a02c0de22e004847b729037f65f8b1632023-04-16T11:17:59ZengNature PortfolioNature Communications2041-17232023-04-0114111910.1038/s41467-023-37652-0Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell deathKeith Woodley0Laura S. Dillingh1George Giotopoulos2Pedro Madrigal3Kevin M. Rattigan4Céline Philippe5Vilma Dembitz6Aoife M. S. Magee7Ryan Asby8Louie N. van de Lagemaat9Christopher Mapperley10Sophie C. James11Jochen H. M. Prehn12Konstantinos Tzelepis13Kevin Rouault-Pierre14George S. Vassiliou15Kamil R. Kranc16G. Vignir Helgason17Brian J. P. Huntly18Paolo Gallipoli19Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonWellcome - MRC Cambridge Stem Cell Institute, University of CambridgeWellcome - MRC Cambridge Stem Cell Institute, University of CambridgeWellcome - MRC Cambridge Stem Cell Institute, University of CambridgeWolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of GlasgowCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonDepartment of Haematology, University of CambridgeCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonDepartment of Physiology & Medical Physics, Royal College of Surgeons in Ireland University of Medicine and Health SciencesWellcome - MRC Cambridge Stem Cell Institute, University of CambridgeCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonWellcome - MRC Cambridge Stem Cell Institute, University of CambridgeCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonWolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of GlasgowWellcome - MRC Cambridge Stem Cell Institute, University of CambridgeCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of LondonAbstract 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.https://doi.org/10.1038/s41467-023-37652-0 |
| spellingShingle | 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 Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death Nature Communications |
| title | Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death |
| title_full | Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death |
| title_fullStr | Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death |
| title_full_unstemmed | Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death |
| title_short | Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death |
| title_sort | mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death |
| url | https://doi.org/10.1038/s41467-023-37652-0 |
| work_keys_str_mv | AT keithwoodley mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT laurasdillingh mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT georgegiotopoulos mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT pedromadrigal mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT kevinmrattigan mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT celinephilippe mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT vilmadembitz mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT aoifemsmagee mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT ryanasby mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT louienvandelagemaat mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT christophermapperley mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT sophiecjames mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT jochenhmprehn mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT konstantinostzelepis mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT kevinrouaultpierre mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT georgesvassiliou mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT kamilrkranc mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT gvignirhelgason mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT brianjphuntly mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath AT paologallipoli mannosemetabolisminhibitionsensitizesacutemyeloidleukaemiacellstotherapybydrivingferroptoticcelldeath |