Scott, M. T. et al. (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15, 651. (doi: 10.1038/s41467-024-44771-9) (PMID:38246924) (PMCID:PMC10800356)
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Abstract
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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This study was supported by Blood Cancer UK (Refs. 14033 and 21004; DV, MC), the Stand Up To Cancer campaign for Cancer Research UK (Ref. C55731/A24896; DV, MC), the Howat Foundation (MC), the Glasgow Experimental Cancer Medicine Centre (funded by Cancer Research UK and the Chief Scientist’s Office, Scotland; MC), and Najran University (Saudi Arabia; HA). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Stevens, Mr Thomas and Dunn, Mrs Karen and Vetrie, Professor David and Almasoudi, Hassan and Scott, Dr Mary and Drotar, Mr Mark and Warren, Felix and Mitchell, Dr Rebecca and Jorgensen, Dr Heather and Pritchard, John and Michie, Professor Alison and Liu, Dr Wei and Kinstrie, Dr Ross and Copland, Professor Mhairi and Clarke, Dr Cassie |
| Authors: | Scott, M. T., Liu, W., Mitchell, R., Clarke, C. J., Kinstrie, R., Warren, F., Almasoudi, H., Stevens, T., Dunn, K., Pritchard, J., Drotar, M. E., Michie, A. M., Jorgensen, H. G., Higgins, B., Copland, M., and Vetrie, D. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Nature Communications |
| Publisher: | Nature Research |
| ISSN: | 2041-1723 |
| ISSN (Online): | 2041-1723 |
| Copyright Holders: | Copyright: © The Author(s) 2024 |
| First Published: | First published in Nature Communications 15: 651 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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