B cell lymphomas in mice with increased deaminase activity
We are partner in a Horizon 2020, Eurostars multisite project involving development of new mouse models for studying the influence of base excision repair (BER) and mismatch repair (MMR) on genome instability in mice with increased deaminase activity. The mouse models will have inactivated tumour suppressor genes in combination with BER and MMR deficiency and induced expression of deaminase activity. The potential mutagenic effect of the genetic modifications in these mouse models is directed towards the B cell compartment. Consequently, mice with the susceptible genotype are expected to develop lymphomas in the B cell compartment with splenomegaly as the most overt marker. We will follow the animals over a 24-month period. The most severe gene combinations may cause lymphomas within a few months. Other gene combinations may not present with any phenotype. The age at which a phenotype presents and the speed at which splenomegaly/lymphoma develops will depend on the genotype of the animal. We expect that only animals with a substantial increase size of the spleen may experience discomfort and poor health.
Deaminases induce lesions in DNA by deamination of cytosine to uracil and is known for its proposed involvement in the development of several cancers e.g. chronic lymphocytic leukaemia (CLL) and breast cancer (Burns et al, 2013 and Maura et al, 2019). Knowledge about the underlying mechanisms of the deaminase activity and the interplay with the DNA repair pathways BER and MMR is wanted. The outcome of this study will allow for development and testing of therapeutic agents, which can break cancer progression at an early time-point of disease. Potentially, this will improve care and quality of life for patients with cancer characterised with upregulated deaminase activity. Scientifically, these new cancer mouse models will fulfil the need for good mouse models to test novel therapeutic agents, which target deaminase activity.
We plan to follow 800 animals including controls. A further 940 animals will be used in breeding to achieve susceptible individuals in only the final generation. Animals will be observed using a scoring sheet upon presentation with signs of discomfort or poor health to evaluate if the animal has reached human endpoints.
Using animal models allow for studying effects of several genetic modifications in a complex multi-organ disease. This cannot be achieved through in vitro research. Still, care is taken to minimize the number of animals used and to catch the affected animals early in disease progression. We consider this set up as a refinement over earlier models.
Deaminases induce lesions in DNA by deamination of cytosine to uracil and is known for its proposed involvement in the development of several cancers e.g. chronic lymphocytic leukaemia (CLL) and breast cancer (Burns et al, 2013 and Maura et al, 2019). Knowledge about the underlying mechanisms of the deaminase activity and the interplay with the DNA repair pathways BER and MMR is wanted. The outcome of this study will allow for development and testing of therapeutic agents, which can break cancer progression at an early time-point of disease. Potentially, this will improve care and quality of life for patients with cancer characterised with upregulated deaminase activity. Scientifically, these new cancer mouse models will fulfil the need for good mouse models to test novel therapeutic agents, which target deaminase activity.
We plan to follow 800 animals including controls. A further 940 animals will be used in breeding to achieve susceptible individuals in only the final generation. Animals will be observed using a scoring sheet upon presentation with signs of discomfort or poor health to evaluate if the animal has reached human endpoints.
Using animal models allow for studying effects of several genetic modifications in a complex multi-organ disease. This cannot be achieved through in vitro research. Still, care is taken to minimize the number of animals used and to catch the affected animals early in disease progression. We consider this set up as a refinement over earlier models.