Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
AI Summary:
Researchers have demonstrated that targeting self-renewal of quiescent leukaemic stem cells (LSC) in chronic myeloid leukaemia (CML) can irreversibly impair LSC function. This could enable more CML patients to discontinue therapy and remain in therapy-free remission.AI Topics:
Whilst it is recognised that targeting self-renewal is an effective way to functionally impair the quiescent leukaemic stem cells (LSC) that persist as residual disease in chronic myeloid leukaemia (CML), developing therapeutic strategies to achieve this have proved challenging. We demonstrate that the regulatory programmes of quiescent LSC in chronic phase CML are similar to that of embryonic stem cells, pointing to a role for wild type p53 in LSC self-renewal. In support of this, increasing p53 activity in primitive CML cells using an MDM2 inhibitor in combination with a tyrosine kinase inhibitor resulted in reduced CFC outputs and engraftment potential, followed by loss of multilineage priming potential and LSC exhaustion when combination treatment was discontinued. Our work provides evidence that targeting LSC self-renewal is exploitable in the clinic to irreversibly impair quiescent LSC function in CML residual disease – with the potential to enable more CML patients to discontinue therapy and remain in therapy-free remission.
Scott, Mary T.
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
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
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listLiu, Wei
Author
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listMitchell, Rebecca
Author
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listClarke, Cassie J.
Author
Fetit, Rana and McLaren, Alistair S. and White, Mark and Mills, Megan L. and Falconer, John and Cortes-Lavaud, Xabier and Gilroy, Kathryn and Lannagan, Tamsin R.M. and Ridgway, Rachel A. and Nixon, Colin and Naiker, Varushka and Njunge, Renee and Clarke, Cassie and Whyte, Declan and Kirschner, Kristina and Jackstadt, Rene and Norman, Jim and Carlin, Leo M. and Campbell, Andrew D. and Sansom, Owen J. and Steele, Colin W. (2024) Characterising neutrophil subtypes in cancer using scRNA sequencing demonstrates the importance of IL-1β/CXCR2 axis in generation of metastasis specific neutrophils. Cancer Research Communications, 4 (2). pp. 588-606. ISSN 2767-9764
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listKinstrie, Ross
Author
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listWarren, Felix
Author
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listAlmasoudi, Hassan
Author
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
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listStevens, Thomas
Author
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
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 listPritchard, John
Author
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listDrotar, Mark E.
Author
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listMichie, Alison M.
Author
Omar, Ramla and Lee, Michelle A.W. and Gonzalez-Trueba, Laura and Thomson, Cameron R. and Hansen, Uwe and Lianos, Spyridonas and Hazarika, Snoopy and El Abdallah, Omar and Ammar, Malak A. and Cassels, Jennifer and Michie, Alison M. and Bulleid, Neil J. and Malfait, Fransiska and Van Agtmael, Tom (2025) The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome. Cell Death Discovery, 11 (1): 200. ISSN 2058-7716
Patterson, Shaun D. and Massett, Matthew E. and Huang, Xu and Jørgensen, Heather G. and Michie, Alison M. (2024) The MYC–NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells. Molecular Oncology, 18 (9). pp. 2234-2254. ISSN 1574-7891
Donnelly, Hannah and Ross, Ewan and Xiao, Yinbo and Hermantara, Rio and Taqi, Aqeel and Doherty-Boyd, W. Sebastian and Cassels, Jennifer and Tsimbouri, Penelope M. and Dunne, Karen M. and Hay, Jodie and Cheng, Annie and Meek, R.M. Dominic and Jain, Nikhil and West, Christopher and Wheadon, Helen and Michie, Alison M. and Peault, Bruno and West, Adam G. and Salmeron-Sanchez, Manuel and Dalby, Matthew J. (2024) Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells. Nature Communications, 15: 5791. ISSN 2041-1723
See full publications listJorgensen, Heather G.
Author
Patterson, Shaun D. and Massett, Matthew E. and Huang, Xu and Jørgensen, Heather G. and Michie, Alison M. (2024) The MYC–NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells. Molecular Oncology, 18 (9). pp. 2234-2254. ISSN 1574-7891
Ramirez-Guzman, Lizbeth A. and Huang, Wenjing and Cole, John J. and Jorgensen, Heather G. (2024) GAS2 upregulation is a targetable vulnerability in chronic myeloid leukaemia. International Journal of Translational Medicine, 4 (2). pp. 354-368. ISSN 2673-8937
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listHiggins, Brian
Author
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. 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 listVetrie, David
Author
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
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listAvailable under License Creative Commons Attribution.
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