Do errors in the production of antibody genes cause mutations that lead to leukaemias with poor survival rates?

The team recently discovered a completely new way in which errors in the production of antibody genes lead tothe development of one type of leukaemia. In this study, the team will capitalise on this to investigate if it also causes disease progression and relapse of similar childhood leukaemias with poorer survival rates. This knowledge is central to developing potentially improved treatments.

The immune system generates millions of antibodies every day to fight vast numbers of potential infections. To create the immense numbers of antibody genes required, different gene segments are taken from one pool and mixed and matched with gene segments from a different pool by breaking and rejoining DNA. Dr Boyes' research discovered a new way mistakes in this process can lead to development of one childhood leukaemia sub-type.

This mechanism involves the DNA by-product that is excised from the genome during theproduction of antibody genes. The recombinase proteins bind to the by-product and the resulting complex then causes cutting of genomic DNA. Following cutting, the cleaved DNA is released whereas the combinase/by-product complex is free to trigger more DNA breaks. The team named this reaction “cut-and-run” and found a very high overlap between the breaks caused by cut-and-run and the mutations present inleukaemia patients.

The leukaemia that we examined has a good five-year survival but for other leukaemias, and for children who relapse, survival rates remain disappointingly poor. Here the team will test if cut-and-run also causes mutations that lead to disease progression and relapse of childhood leukaemias with poor survival rates. This will determine whether inhibitors of cut-and-run could provide vital new tools in the battle against themost serious childhood leukaemias. The team will additionally test if threshold levels of the recombinase and by-product collectively providediagnostic markers for disease progression.

Such knowledge may enable more targeted, potentially milder,initial patient treatments.