The challenge

Professor David Vetrie, University of Glasgow, aims to take his new grant project a step further. Not only will his team continue to study TR1 and TR2 leukaemic stem cells to improve prediction of treatment response, but also development new targeted therapies.

Professor David Vetrie

Chronic myeloid leukaemia (CML) is a type of blood cancer caused by the Philadelphia chromosome, which creates a type of fusion (two genes joined) gene called: BCR-ABL. This fusion gene causes myeloid white blood cells to multiply uncontrollably in the bone marrow. This process starts through faulty stem cells who acquire the Philadelphia chromosome which created the BCR-ABL. These faulty cells lead to the production of too many white blood cells that cause problems such as anaemia, infections, and bleeding.

Despite tremendous improvements in CML patient care, which has been achieved by medication such as the introduction of tyrosine kinase inhibitors e.g. imatinib, treating CML today is not without challenges. These drugs don’t work well in some patients and other patients have drug side effects like vomiting, headaches, and bleeding. There is still significant clinical need for 70% of all chronic phase patients, who are either resistant or intolerant to tyrosine kinase inhibitors, or who respond optimally but cannot achieve treatment-free remission due to persisting leukaemia stem cells which are not destroyed by the medication.

The science behind the research

Professor Vetrie’s group has identified subsets of leukaemic stem cells (LSCs) present in all chronic phase (CP) patients that have the ability to follow different blood cell development pathways. Similar to travelling from London to Glasgow via two different sets of motorways, such as the M6 or the A1(M). Both routes reach the same destination, but the path taken along the way is different. These subsets are referred to as TR1 and TR2 LSCs. The levels of TR1 and TR2 can distinguish patients who respond optimally to treatment from those who do not, meaning they could potentially serve as valuable predictive biomarkers.

In his previous Project Grant funded by Leukaemia UK, Professor Vetrie and his team identified cytokine-mediated signalling (small protein messengers in the body) as a key regulator of TR1 cells and of optimal responses to tyrosine kinase inhibitors.

In this new project, Professor Vetrie aims to take the research a step further. His team will continue to study TR1 and TR2 leukemic stem cells to strengthen their predictive value, identify the key cytokines that regulate them, and begin developing new therapeutic strategies designed to eliminate these cells.

What difference will this research make?

In the medium-term, Prof. Vetrie hopes that CML patients will start to directly benefit from the work through access to early phase clinical trials. The team will continue to engage closely with clinical colleagues in Glasgow, Scotland and with the broader CML clinical community in the UK.

In the long term, this work aims to improve the clinical management of CML, whether through standard-of-care TKI therapy or newer treatments, to benefit as many patients as possible. This could be achieved through the use of predictive biomarkers to guide treatment decisions – identifying which patients are likely to respond and which are not. For those unlikely to benefit, this would enable earlier redirection to alternative or clinical trial therapies that may be more effective. Additionally, these insights may help explain the variability in treatment response, particularly why leukaemia stem cells are successfully targeted in some cases but not in others.

It is encouraging to see the progress made from the first project grant, with discoveries from this work now leading to a new grant that could together, help improve patient management, support more personalised care, and potentially lead to novel treatment approaches for CML.