Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease.
Mary T ScottWei LiuRebecca MitchellCassie J ClarkeRoss KinstrieFelix WarrenHassan Hussain AlmasoudiThomas StevensKaren M DunnJohn PritchardMark E DrotarAlison M MichieHeather G JørgensenBrian HigginsMhairi CoplandDavid VetriePublished in: Nature communications (2024)
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.
Keyphrases
- stem cells
- chronic myeloid leukemia
- embryonic stem cells
- end stage renal disease
- wild type
- induced apoptosis
- cancer therapy
- human health
- newly diagnosed
- primary care
- bone marrow
- neural stem cells
- signaling pathway
- chronic kidney disease
- dendritic cells
- peritoneal dialysis
- transcription factor
- cell cycle arrest
- rheumatoid arthritis
- risk assessment
- mesenchymal stem cells
- cell death
- drug delivery
- systemic lupus erythematosus
- ulcerative colitis
- immune response
- combination therapy
- patient reported