Before leukemia develops, there are often precursors, so-called pre-leukemias. For a long time, however, it was not fully understood how leukemia actually develops from a pre-leukemia. Using the model of childhood leukemia in children with Down's syndrome ("trisomy 21"), an international research group has now demonstrated in a large functional study the mechanisms of transformations from precursors to complete pronounced leukemia.
Prof. Dr. Jan-Henning Klusmann, head of the study and director of the University Clinic and Polyclinic for Paediatrics I at The University Hospital Halle (Universitätsklinikum Halle, Saale, Germany) has been researching leukemia in children for a long time, especially in children with Down's syndrome. "Overall, to our knowledge, this is the most comprehensive and complete genetic characterization of any type of cancer. There is no study that determines the mutations in such a large cohort of 218 patients and subsequently examined the mutations found for their cancer-promoting potential. However, our results show that this is extremely important," said Dr. Klusmann.
There have already been large studies that have sequenced the cancer genome in patient cohorts. However, in addition to the mere description of mutations, it is also important to understand the genetic variants and their influence during the development of cancer. Childhood leukemia is an excellent model for this, because there are different precursors at different times, making it possible to investigate pre-leukemia and leukemia separately, Dr. Klusmann continued.
According to the research group, many years of previous research have shown that about one-third of children with Down's syndrome (DS) have precursors of leukemia, which is usually associated with an acquired mutation of the so-called GATA1 gene. One-fifth of these children develop myeloid leukemia, typically when additional mutations are added. In the sequencing study, patient samples of leukemia groups from Great Britain, Germany, Japan, and the USA were examined.
The genetic data set was then used as a platform for targeted, comprehensive functional studies to understand the significance of the identified variants. "We've targeted the mutations into blood cells. Among other things, we used the CRISPR/Cas9 system, the gene scissors, for this," says Klusmann. "Such investigations were not possible five or six years ago, i.e. before the discovery of the genetic scissors."
The results showed that many of the mutations found - particularly in pre-leukemia - had no effect at all on stem cells. On the other hand, new mutations have been found that affect, for example, a cytokine receptor.
In their experiments with blood stem cells, the scientists led by a pediatric oncologist showed that the mutation in the cytokine receptor causes the uncontrolled growth of immature cells. Using the CRISPR-Cas9 system, the scientists also shed light on the interaction of mutations in cytokine receptors or their downstream signaling pathways with mutations in factors that organize the genome. Thus new therapy possibilities could be pointed out.
"The altered cytokine receptors and their signaling pathways, as well as the epigenetic factors, are suitable therapeutic targets. There are drugs available or are currently being developed that specifically inhibit these enzymes," concluded Klusmann. "So we hope to improve the therapy for the affected children in the future."