In a new paper published in Nature Communications, researchers from the Roy, Roberts and Milne groups describe a novel technique for modelling a rare infant cancer, a method that has been 20 years in the making.
Acute Lymphoblastic Leukaemia (ALL) is a cancer affecting white blood cells, and is one of the commonest cancers in children. Advances in the detection and treatment of ALL have led to mortality rates for this leukaemia decreasing by almost half since the 1970s (CRUK). Indeed, survival rates of children with ALL have risen to 90%. However, for infants under the age of 1 with the disease, the outcome looks very different. Infant ALL is more aggressive and less responsive to treatment, which means only 5-6 out of 10 babies with ALL can be cured.
“The unique biology of infant ALL is likely to depend on the specific developmental features of the prenatal cells that it arises in, and is one of the reasons why it has been so difficult to model this disease. Using the right human cell context was very important to generate an accurate model that can be used to understand infant ALL.” said Prof. Andi Roy, Associate Professor of Paediatric Haematology, and senior co-author of the paper.
In order to model this disease, the team led by Associate Professors Thomas Milne and Andi Roy from the MRC Molecular Haematology Unit and Department of Paediatrics focussed on a genetic change found in around 70% of infant-ALL cases whereby chromosomes become rearranged. By introducing this specific genomic rearrangement in immature human prenatal blood cells using CRISPR-Cas9 techniques, the group was able to accurately recapitulate the clinical and molecular features of infant ALL.
The research also sheds a light on why infant leukaemia is more aggressive. The genetic alteration on which the model is based, a rearrangement of the Mixed Lineage Leukemia (MLL) gene is also found in some older children with ALL, but their prognosis is often better. The reasons underlying this difference were previously unclear. Here the researchers demonstrate that fetal gene expression programmes are retained in infant ALL but not childhood ALL, and may provide a molecular landscape that allows development of a more aggressive disease.
It is hoped this powerful model will facilitate further insights into the initiation and unique characteristics of infant ALL, and be a very useful preclinical model to manipulate vulnerabilities in infant ALL cells, and test novel therapies.
“For the first time, we have a model where we can carefully map out the molecular details of this aggressive disease.” Says Professor Thomas Milne, Associate Professor of Haematology. “This provides us with a powerful platform for not only testing new therapies, but also better understanding how the disease arises in the first place”
This research was funded by the Medical Research Council (MRC), Blood Cancer UK, Wellcome Trust and funding to individual authors. Work by Professor Irene Roberts, Professor Thomas Milne and Professor Anindita Roy is also supported by the NIHR Oxford Biomedical Research Centre.
Read the full paper in Nature Communications: