Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
AI Summary:
Mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells. Inhibition of mitochondrial 1C metabolism has a cytostatic effect on chronic myeloid leukaemia cells.AI Topics:
Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.
Zarou, Martha M.
Author
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
See full publications listRattigan, Kevin M.
Author
Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
Rattigan, Kevin M. (2024) Mini review of metabolism in leukaemia: from complexity to the clinic. Frontiers in Hematology, 2: 1353994. ISSN 2813-3935
See full publications listSarnello, Daniele
Author
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
Rattigan, Kevin M. and Zarou, Martha M. and Brabcova, Zuzana and Prasad, Bodhayan and Zerbst, Désirée and Sarnello, Daniele and Kalkman, Eric R. and Ianniciello, Angela and Scott, Mary T. and Dunn, Karen and Shokry, Engy and Sumpton, David and Copland, Mhairi and Tardito, Saverio and Vande Voorde, Johan and Mussai, Francis and Cheng, Paul and Helgason, G. Vignir (2023) Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells. EMBO Reports, 24: e56279. ISSN 1469-221X
See full publications listShokry, Engy
Author
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
Rattigan, Kevin M. and Zarou, Martha M. and Brabcova, Zuzana and Prasad, Bodhayan and Zerbst, Désirée and Sarnello, Daniele and Kalkman, Eric R. and Ianniciello, Angela and Scott, Mary T. and Dunn, Karen and Shokry, Engy and Sumpton, David and Copland, Mhairi and Tardito, Saverio and Vande Voorde, Johan and Mussai, Francis and Cheng, Paul and Helgason, G. Vignir (2023) Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells. EMBO Reports, 24: e56279. ISSN 1469-221X
See full publications listDawson, Amy
Author
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723
See full publications listIanniciello, Angela
Author
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723
Rattigan, Kevin M. and Zarou, Martha M. and Brabcova, Zuzana and Prasad, Bodhayan and Zerbst, Désirée and Sarnello, Daniele and Kalkman, Eric R. and Ianniciello, Angela and Scott, Mary T. and Dunn, Karen and Shokry, Engy and Sumpton, David and Copland, Mhairi and Tardito, Saverio and Vande Voorde, Johan and Mussai, Francis and Cheng, Paul and Helgason, G. Vignir (2023) Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells. EMBO Reports, 24: e56279. ISSN 1469-221X
See full publications listDunn, Karen M.
Author
Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723
See full publications listCopland, Mhairi
Author
Copland, Mhairi (2024) Triplet therapy for advanced BCR::ABL1 positive myeloid leukaemias. Lancet Haematology, 11 (11). e807-e808. ISSN 2352-3026
Innes, Andrew I. and Hayden, Chloe and Orovbon, Victoria and Claudiani, Simone and Fernando, Fiona and Khan, Afzal and Rees, David and Byrne, Jennifer and Gallipoli, Paolo and Francis, Sebastian and Copland, Mhairi and Horne, Gillian and Raghavan, Manoj and Arnold, Claire and Collins, Angela and Cranfield, Tanya and Cunningham, Nicholas and Danga, Akila and Forsythe, Peter and Frewin, Rebecca and Garland, Paula and Hannah, Guy and Avenoso, Daniele and Hassan, Sandra and Huntly, Brian J.P. and Husain, Jissan and Makkuni, Sudhakaran and Rothwell, Kate and Khorashad, Jamshid and Apperley, Jane F. and Milojkovic, Dragana (2024) Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy. Leukemia, 38 (11). pp. 2443-2455. ISSN 0887-6924
Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234
See full publications listSumpton, David
Author
Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
See full publications listVazquez, Alexei
Author
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
See full publications listHelgason, G. Vignir
Author
Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234
Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723
Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723
See full publications listAvailable under License Creative Commons Attribution.
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