Investigating how DNA cutting errors lead to childhood leukaemia coming back after treatment

Despite improved outcomes for most childhood leukaemias, the overall survival for high-risk leukaemia remains low. The main cause of this is the cancer returning after treatment (relapsing), which can be due to the cancer gaining DNA mutations and becoming resistant to treatment. We urgently need to find improved ways to prevent treatment resistance.

In this project, Dr Joan Boyes from the University of Leeds will be looking at a way to prevent these genetic errors that lead to relapse. She believes that the immune system is responsible for most of the genetic mutations in childhood leukaemia.

The immune system generates millions of antibodies every day by cutting out tiny pieces of genes to ‘mix and match’ together, which involves breaking and re-joining DNA. The immune system uses an enzyme called ‘recombinase’ to cut the DNA, but Dr Boyes’ team found that this enzyme joins up with the left-over parts of the cut DNA, creating a dangerous by-product that randomly cuts genetic material. Recombinase can also join the wrong pieces of DNA together, leading to more genetic errors.

Dr Boyes’ team know that if a child has more of the recombinase enzyme, then they are more likely to relapse. Therefore, they want to discover how the enzyme is causing these mutations, and which mutations are contributing to relapse. They will look at the mutations in patients’ whole genome sequences data, and then combine this with their leukaemia samples to look at the impact of these mutations on leukaemia cell activity and processes. By looking at diagnosis and relapse samples from high-risk leukaemias, the team can find out how many of the mutations actually occur after diagnosis, leading to relapse.

They also hope to find out whether blocking some of the recombinase reactions, where the enzyme binds to leftover DNA, could prevent relapse in some patients. Drugs that stop the enzyme from binding to the DNA could be a valuable tool in fighting against leukaemia. Dr Boyes hopes that this project will therefore provide vital information about new ways to target leukaemia cells to reduce relapse and create safer treatments.