We are interested in understanding what is the aetiology of childhood leukaemias, how they develop the disease. It has been shown that for the majority of cases childhood leukaemia is a result of the combination of two hits, two genetics events. The first event is the acquisition of genetic susceptibility that could be acquired in utero, before birth. This first event transforms a normal, healthy cell into a preleukaemic clone. It has been shown that this preleukaemic clone could be present in up to 5% of newborns, so it’s quite a high percentage. But the incidence of the disease is lower so we need a second hit to take place to fully transform this preleukaemic clone into a full-blown leukaemia.
We have shown in our lab that the exposure to infections could trigger the development of leukaemia in predisposed mice. We have exposed preleukaemic mice in order to rule out how infection can develop the disease. We have proved in our lab that infection is able to develop leukaemia in predisposed carriers.
So now we wanted to understand how infection is able to do so and this is why we have conducted this latest research in which we have proved that gut microbiome is playing a critical role in this infection interaction to the preleukaemic clone in order to develop the disease. This is more or less the background of the research.
What were the methods?
We have used genetically predisposed mice, these are Pax5 heterozygous mice. This is a genetic predisposition that could be present or is also found in children in humans. So these mice when they are exposed to infection develop leukaemia. In order to understand the role of the gut microbiome we have used the analysis of the gut microbiome of these mice. The main method has been used to sequence the microbes present in the gut and we have also analysed drugs by treating these mice with antibiotics as antibiotics are able to remove the gut microbiome.
What were the main findings?
The main findings that we found in our research are that the depletion of the gut microbiome by the treatment of antibiotics of predisposed mice increased the incidence of the disease. Even more, we have seen that predisposed mice have a different microbiome to wildtype mice, not predisposed carriers. So we have also been able to predict the genetic predisposition of the mice just based on the gut microbiome. We found an accuracy of 96%, so it’s very high. We think that the gut microbiome could be used as a biomarker to detect which are the predisposed carriers that are more prone to develop the disease than among others.
What are the main conclusions?
We have to keep in mind that these results have been conducted in mice but it is also true that these mice develop a leukaemia very similar to humans. They have the phenotype of these mice and also genetically these leukaemias are very similar to humans. So we need to validate these results in humans, that could not be so easy but we need to validate it, of course.
I would speculate that maybe predisposed humans, with a genetic predisposition, if they are treated with antibiotics we can modify the gut microbiome of these carriers in such a way that we can make them more prone to develop leukaemia than others. So maybe the use of antibiotics in predisposed carriers could be taken in mind – we think about that, maybe it’s not a good idea to over-treat predisposed carriers with antibiotics in order to prevent leukaemia development.
Also maybe in the future if we can validate the role of the gut microbiome in childhood leukaemia development maybe we can modify the gut microbiome in patients, predisposed carriers, and make them more resistant to full transformation. It could be a preventive strategy to developing childhood leukaemia.
Did you discover any particular bacteria that were protective against the leukaemia?
Yes, that would be great but we haven’t identified a specific bacteria. We have found a pattern of different bacteria and families of micro-organisms but not the specific one. So we cannot use a single bacteria to maybe modulate the gut microbiome. So it’s the whole composition of the gut microbiome.
What are the next steps?
This is something that we are planning to do, to see if predisposed carriers in humans also have a different gut microbiome. It would be great to find an epidemiological correlation between the intake of antibiotics and the development of leukaemia. There has not been published anything so far so maybe just to look a bit, depending on the current studies, and maybe to conduct new ones.
This study has been done in collaboration with two groups, not only the one from the Institute of Biomedical Research in Salamanca in Spain but also with Professor Arndt Borkhardt in the University of Düsseldorf in Germany. So it’s a tight collaboration between these two groups in Spain and in Germany. I would like to emphasise that.