29 June 2022

Scientists have discovered one way to target leukaemia stem cells in acute myeloid leukaemia (AML), without harming healthy stem cells – which could lead to a new and safer way to treat the disease.

Dr William Grey from the University of York led the research studying patient samples in the lab and in mice. Grey and colleagues found that targeting CKS1 could simultaneously kill AML leukaemia stem cells (LSCs) while protecting healthy haematopoietic stem cells from the effects of chemotherapy. This improved treatment responses and reduced chemotherapy side-effects.

He said the findings could lead to new treatment methods that will also see patients experiencing far fewer side effects compared to traditional chemotherapy. It is hoped the new approach could increase survival rates and lead to opportunities to bring back elderly and clinically unfit patients into a selection criterion for intensive therapy.

Grey and his colleagues say identifying a new vulnerability in leukemic stem cells could lead to strategies that exploit this weakness, which may help to reduce relapse rates and improve treatment outcomes.

Writing in Science Translational Medicine, they say the same inhibitor also protected healthy stem cells grafted into mice, and protected the cells from the toxic effects of doxorubicin and cytarabine.

Mice with acute myeloid leukaemia that received these two drugs alongside the CKS1 inhibitor survived for longer and had higher amounts of healthy stem cells, compared with control mice that only received doxorubicin and cytarabine.

The drug accelerated the production of cell-killing reactive oxygen species in leukaemic stem cells.

The team add that other types of solid tumours have also been linked to overexpression of the CKS1B gene, which suggests CKS1 inhibitors could have a broader application.

Dr Grey, from the Department of Biology at the University of York and the Francis Crick Institute in London, said: “We hope that this work will open new avenues of investigation into the protein dynamics of stem cells, and give us a better understanding of how stem cells work in our body and how they go wrong during disease.

“In doing so we hope to reveal new and more effective treatment targets that haven’t yet been discovered during the genetic revolution that has been ongoing for the past two decades.”

Fiona Hazell, chief executive of Leukaemia UK, one of the charities that funded the study, added: “We know that research has the power to stop leukaemia devastating lives, but that more still needs to be done to find kinder and more effective treatments, especially for acute leukaemias.

“Dr Grey’s promising discovery, during his Leukaemia UK John Goldman Fellowship, demonstrates the importance of continued research in this area and could go on to provide a vital new treatment option for leukaemia patients.”

The team are looking to develop the new approach and hope to start a clinical trial with the Royal Marsden Hospital in London.

Source: Grey W, Rio-Machin A, Casado P, Grönroos E, Ali S, Miettinen JJ, Bewicke-Copley F, Parsons A, Heckman CA, Swanton C, Cutillas PR, Gribben J, Fitzgibbon J, Bonnet D. (2022) “CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukaemia.” Science Translational Medicine, doi: 10.1126/scitranslmed.abn3248

Link: http://www.science.org/doi/10.1126/scitranslmed.abn3248

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