Stopping ‘cut-and-run’ DNA errors to help treat leukaemia and predict relapse

The immune system needs to generate millions of antibodies every day to fight a vast number of potential infections. Dr Boyes team has recently discovered a completely new way in which mistakes in this process can lead to childhood leukaemia – called ‘cut-and-run’ errors. This new project develops this latest understanding by testing two distinct approaches with the goal to help improve patient care.

To create the huge variety of antibody genes required to fight infection, different pools of gene segments are ‘mixed and matched’ with each other, in a process of breaking and re-joining DNA. The body uses an enzyme called ‘recombinase’ to ‘cut’ the DNA, but Dr Boyes’ team found that sometimes this enzyme joins up with the left-over parts of the cut DNA, creating a highly dangerous new product that can cause random cuts in genetic material.

Acute lymphoblastic leukaemia (ALL) is caused by a series of changes (‘mutations’) in specific genes. Although five-year survival for childhood leukaemia is very good, for children who relapse, the survival rate is poor. Dr Boyes’ team have found that many of the genes that are mutated during relapse are also targets of the ‘cut-and-run’ by-product, suggesting that the ‘cut-and-run’ process could contribute to relapse.

In their new project the team will test to see if increased levels of the ‘cut-and-run’ by-product at diagnosis are associated with increased risk of relapse. If this is the case, it could provide a new diagnostic marker for relapse, thus enabling more targeting of patients’ treatment. A second part of the project will look to develop new products that can inhibit the ‘cut-and-run’ by-products, providing a new tool in the battle against leukaemia, and in particular, against relapse.