British researchers have identified key genetic changes in leukocytes that may explain the development of paediatric acute lymphoblastic leukaemia (ALL) during antibody production.
The Leeds-based study has pinpointed errors in recombination that lead to the cells becoming cancerous – and offers an explanation of how infection can trigger the development of disease.
During the production of antibodies, the enzymes RAG1 and RAG2 ‘shuffle’ sections of DNA to produce unique antibodies. A by-product of this process is the production of short pieces of waste DNA. According to the study, these DNA by-products can bind with RAG1 and RAG2 to form “highly dangerous” complexes, leading to random alterations to the genome. The researchers call this process ‘cut-and-run’.
The researchers say the process explains some of the secondary mutation that occur in ETV6/RUNX1 leukaemia, which is responsible for about 25% of the cases of paediatric ALL.
They reported their findings in the journal Molecular Cell.
Researcher Dr Joan Boyes, from Leeds University, said: “The price we pay for such an effective immune system is that occasionally mistakes can be made that can cause blood cancers to develop. Now that we know exactly how this process works, we may be able to stop it – leading to new drugs to treat children in the future.”
Dr Alasdair Rankin, Director of Research and Patient Experience for the charity Bloodwise, which funded the study, said: “We know that childhood leukaemia needs at least two steps to develop and some evidence suggests that the second trigger occurs when a child’s immune system reacts in an abnormal way to infections. As important research like this helps build a more complete picture of what causes childhood leukaemia, we can begin to think about ways to stop it happening in the first place.”
Source: Kirkham, C.M., Scott, J.N.F., Wang, X., Smith, A.L., Kupinski, A.P., Ford, A.M., Westhead, D.R., Stockley, P.G., Tuma, R., Boyes, J. (2019) “Cut-and-Run: A distinct Mechanism by which V(D)J Recombination causes Genome Instability”, Molecular Cell, available from doi: 10.1016/j.molcel.2019.02.025
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