Rationale
Lymphoid cancers develop in white blood cells and are the fourth most common cancer with over 15,000 new cases each year in the UK alone.
A frequent cause of these cancers is mistakes in the production of antibody genes. During the production of these genes, individual gene segments are selected from separate large collections of gene segments. These are then joined together in a process known as V(D)J recombination. The vast number of different combinations of gene segments that become joined generate genes that encode millions of different antibodies. However, because the reaction involves the breakage and rejoining of DNA, the wrong pieces of DNA can become joined, leading to the activation of cancer-causing genes. Hence, it is important to understand what regulates the normal V(D)J recombination reaction to then understand how the wrong pieces of DNA are selected for joining. We are investigating this using mouse models in which the V(D)J recombination reaction can be induced. Specifically, we breed genetically modified mice, sacrifice them and expand the white blood cells in the laboratory prior to induction of recombination and analysis of how the reaction is regulated. These experiments expand our current work, including one set of experiments that explores a novel cancer-causing mechanism that we recently discovered in our laboratory.
Plan of work and impact of our studies
We have generated various genetically modified mouse lines for these experiments. It is necessary to use some animals in this work since tissue culture systems do not exist that faithfully recapitulate the regulation of the production of antibody genes. The mouse models we have developed allow us to follow the V(D)J recombination reaction step by step and to investigate how mistakes in the regulation of V(D)J recombination lead to lymphoid cancers. The longer term goal is to be better able to reduce the incidence of these cancers.
Animal welfare
To reduce the number of animals (by 10-15 fold), we routinely increase the numbers of primary cells obtained from mice by growing them in culture prior to performing the experiments.
We have also generated a cell line from one of the main mouse models. This has replaced about 300 animals per year. However, since the cell line is not perfect, we still need to use animals for some experiments. Most of the work is of sub-threshold to mild severity and involves only the maintenance of genetically modified mice that are socially housed in a state-of-the-art facility with plenty of environmental enrichment.
Non-technical summary
Read regulation of V(D)J recombination, antibody generation and transcription non-technical summary (PDF).
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