Thank you very much for this nice introduction and I feel very honoured that our work experiences so much interest here and would really like to invite you to the full presentation of this abstract later on today in the Presidential lecture.
We are interested in the connection of acute lymphoblastic leukaemia in childhood and exposure to infection. Acute lymphoblastic leukaemia is still the major type of cancer in childhood and remains a major cause of death in these young children. We have a specific age peak during 2 to 6 years in children who develop acute lymphoblastic leukaemia and this is an age peak which we do not observe in other types of childhood leukaemia. There are many hypotheses around why we have this age peak but there are no very good explanations right now. So exposure to infection is one hypothesis which is going on since decades and was first proposed at the beginning of the twentieth century as a trigger of leukaemia. However, the mechanism, how exposure to infection triggers leukaemia, is not yet known. On the other hand, knowing how infection can trigger leukaemia would offer a lot more options for prevention or even better for the treatment of leukaemia.
However, we do not think that leukaemia or exposure to infection alone is causing leukaemia because when we consider that more than eight infectious episodes are supposed to be physiologic in young children then we would expect many more children to suffer from leukaemia if it would be just exposure to infection. We hypothesised that it’s more exposure to infection on a susceptible genetic background. So children who carry a genetic predisposition, meaning a germline predisposition which is inherited from the parents, or maybe an in utero acquired early genetic lesion like the TEL-AML fusion which is probably the most well-known and most common subtype in childhood leukaemia.
We tried to address this question of exposure to infection and leukaemia development in two different mouse models, the cytogenetically modified mouse models, which we present a rare subtype of childhood leukaemia with PAX5 loss of function mutations, and the most common subtype of childhood leukaemia represented by the TEL-AML1 fusion protein. These mice do not develop leukaemia by itself and what we did is we exposed the mice to a common infection environment. So either we held the mice in a pathogen free animal facility or we exposed them just to a common infectious environment. What is important is that we did not inject the mice with a specific pathogen, they were really only transferred from a very clean environment to just a common infectious environment. What we did is we monitored leukaemia development and the mechanism, how leukaemia evolves from a pre-leukemic clone after the clone was triggered by infection.
What we observed is that leukaemia only developed in the mice which were transferred to the common infection environment. We did not observe leukaemia development in these mice when they were held in the pathogen free facility. The leukaemia we observed mimicked very much the phenotype of the human leukaemia, the leukaemia we observed in our children, however the mechanism, so the mechanism that takes place in the pre-leukemic cells after the mice were exposed to infection, was different in the two mouse models. So the mechanism is definitely dependent on the genetic predisposition which is present from the beginning on.
To conclude, acute lymphoblastic leukaemia can be trigged by exposure to infection which was shown in two different mouse models. The mechanism of leukaemia development is different and is based on the genetic predisposition. We definitely need a genetic predisposition in order to give exposure to infection the chance to develop leukaemia. This is another piece that will hopefully contribute to the picture of how exposure to infection can contribute to leukaemia development and will pave the way for novel approaches for treatment and hopefully, even better, for the prevention of acute lymphoblastic leukaemia in childhood. Thank you very much.
