Around 3,000 people in the UK are diagnosed with acute myeloid leukaemia (AML) each year, and roughly half of those with the t(8;21) subtype will relapse because dormant leukaemic stem cells (LSCs) survive chemotherapy and later reawaken. The core problem is that doctors cannot tell which residual cancer cells will cause relapse and which are harmless. This uncertainty forces some patients into unnecessary, risky bone marrow transplants while others miss timely treatment. No existing drugs target LSC regrowth specifically. This project will map the growth signals that wake up LSCs in different AML subtypes. By sequencing single cells from patient samples, the team will identify which pathways—beyond the VEGF and IL-5 signals already found in t(8;21) AML—trigger LSC reactivation. They will then test whether existing drugs can block those pathways. If successful, the work could produce two concrete outputs: drug targets to prevent relapse, and a blood test that detects only the dangerous residual cells, making relapse prediction far more accurate. This is fundamental science with a clear translational path—understanding the precise molecular switches that turn dormant cancer cells back into growing tumours.
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Blood cancers such as Acute Myeloid Leukaemia (AML) are challenging to treat. Around 3000 adults and children are diagnosed in the UK each year and survival is variable, but overall poor. Relapse is the most important singular cause of treatment failure in AML. This project asks how we can prevent relapse. In AML, primitive blood cells grow out of control in the bone marrow and blood. Chemotherapy is used to kill these cells. Some dormant cancerous cells, called leukaemic stem cells (LSCs) are not killed by chemotherapy, but can start growing again later when they receive the right signal. Reactivation of LSCs after patients achieve remission leads to relapse, typically with an even more aggressive and difficult to treat cancer. We do not know why LSCs begin to grow again and because they are rare, they are difficult to study. There are currently no treatments specifically targeting LSC regrowth. Some patients continue to have low levels of cancer cells in their blood and bone marrow after treatment, which is associated with a higher chance of relapse and requires monitoring with regular bone marrow samples. Whether these cells are always dormant LSCs capable of causing relapse or other, residual cells which cannot cause relapse is unknown. This lack of understanding can lead to missed treatment opportunities or unnecessary, risky, and expensive bone marrow transplantation. Relapse is therefore difficult to predict, prevent or treat. AML is caused by a variety of genetic mutations leading to different AML subtypes which behave differently. In one type of AML, known as t(8;21), around 50% of patients relapse and circulating blood cancer cells often remain after treatment. We have shown that the signals which activate the growth of t(8;21) LSCs are the VEGF and IL-5 pathways, which act via the signalling responsive AP-1 transcription factor family. These pathways are not normally active in healthy blood stem cells, but are switched on in t(8;21) LSCs as a result of the AML-causing mutation. Due to the specific gene expression patterns caused by each genetic mutation, we hypothesise that there will be other AML subtype-specific pathways which lead to LSC reactivation. To find which signals could activate LSC growth in AML subtypes other than t(8;21), we will carry out single cell RNA-sequencing to examine gene expression in sorted LSCs from patients with three further molecular subtypes. We will use this to identify which growth factor pathways are LSC-specific in each type and perform functional assays to test if they activate AP-1 and promote growth. Where available, inhibitory drugs of these pathways will be used to test if LSC reactivation can be prevented. Newly transcribed genes from the LSCs will be captured following stimulation of the identified growth pathways. Integrating this information with our single cell sequencing data will let us identify precisely how LSCs begin to grow by finding which genes are activated. In parallel, the aberrantly expressed growth pathways will be used to improve existing methods for detecting cancerous blood cells and predicting relapse, by measuring only those cells which will go on to cause AML regrowth. Together this program of work will produce: LSC-specific therapeutic targets to block growth and prevent relapse. A platform using these novel, functional biomarkers to predict relapse more accurately. Mechanistic insights into how the relapse causing LSCs grow.
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