|  | | |  Dr Alice Norton was awarded our Clinical Research Training Fellowship to study the genetic link between childhood leukaemia and Down's syndrome. She is based at the Weatherall Institute of Molecular Medicine, in Oxford, where she has been working with Dr Paresh Vyas on a Leukaemia Research funded project that aims to directly influence the clinical management of leukaemia for children with Down's syndrome, but will also impact on childhood cancer in general.
As their project is nearing a close the pair discuss the outcomes of their work in a recent interview.
What is the link between leukaemia and Down's syndrome?
Down's syndrome is the most common genetic condition in the UK caused by the presence of an extra chromosome and affects 750 newborn babies every year. It is linked to the onset of a number of genetic abnormalities including leukaemia, which itself is the most common form of childhood cancer. About 1% of children with Down's syndrome will go on to develop leukaemia.
What sort of leukaemia do children with Down's syndrome develop?
Children with Down's syndrome have an increased risk of developing leukaemia. One form of leukaemia that is particularly prevalent in children with Down's syndrome is called acute megakaryocytic leukaemia (AMKL). Children with Down's syndrome are also affected by another form of leukaemia called acute lymphoblastic leukaemia (ALL), which is the most common childhood cancer affecting around 450 children in the UK every year.
How does the development of leukaemia differ between children with and without Down's syndrome?
Leukaemia develops through a build up of genetic mutations that result in cancerous blood cells being made in place of healthy blood cells. It is not yet known why these mutations occur but recent research has shown that some of the changes must happen while the foetus is developing, so before the child is even born. These children are born in a ‘pre-leukaemic’ condition, but further changes are required before actual leukaemia is diagnosed. This is the case for both AMKL and probably also for ALL. To date, we know more about the genes involved in the development of AMKL.
What is known about the genetics behind leukaemia in children with Down's syndrome?
Around 2-10% of children with Down's syndrome are born with a blood condition called Transient Myeloproliferative Disorder (TMD) and 30% of these will go on to develop AMKL. Thus, it is clear that TMD is the pre-leukaemic condition. This has been confirmed by the identification of a genetic mutation in a transcription factor called GATA1 that is important in controlling blood cell development. Mutations in GATA1 are seen both in patients with TMD and AMKL, but not in other forms of leukaemia such as ALL.
What is being done to identify children with Down's syndrome who are at risk of developing leukaemia?
A large proportion of children born with a pre-leukaemic condition will never show any disease symptoms or require treatment as the leukaemia seems goes away. This has been easy to observe in children born with Down's syndrome because it comprises such a clearly defined population. However, for a number of these cases full leukaemia can develop in early childhood. Currently, there is no clinical strategy to identify children with Down's syndrome born with TMD. We are therefore hoping that the results of our study will increase awareness for the need to screen this group of children for the pre-leukaemic condition, thereby identifying those most at risk of developing leukaemia in later childhood.
Is it feasible to introduce routine blood screening?
Yes, we think it is and this campaign has already received a good response within the clinical community. Children with Down's syndrome are already being tested for a number of other conditions, but leukaemia seems to have been overlooked. We hope that routine screening will be introduced to identify those children with the pre-leukaemic condition. This will allow clinicians to monitor them and diagnose the leukaemia at an early stage. We are then considering the possibility of introducing low dose out-patient chemotherapy to children at high risk of developing AMKL to prevent the onset of leukaemia. This would be a completely novel approach to prevent leukaemia occurring. This is important because when children develop AMKL they need several months of in-patient high dose chemotherapy. Though this is effective, it would be nice to avoid giving young children this intensive chemotherapy, which can have severe side effects and a small proportion do die as a result of this treatment.
How have you been conducting your study?
We have been collecting samples from across the UK using centres based here in Oxford as well as Leeds and Scotland. So far we have 160 samples, but are aiming to collect at least 300 by the end of the study and are very pleased by the progress we have made. We take a blood sample at birth and analyse it for the presence of abnormalities. We are focusing on TMD but are also hoping to build a broader picture of the blood in infants with Down's syndrome. We then take another sample a few months later to track any changes. Both samples are taken in conjunction with other routine blood tests to avoid any additional tests and unnecessary discomfort for the child. We then follow the individuals until the age of five as AMKL rarely, if ever, occurs after the age of five. The families approached have been very cooperative and are happy to participate and engage with our study.
How will this contribute to our understanding of childhood leukaemia in general?
This is the good example of a molecular test to predict the likely development of leukaemia in children. We hope to identify other genetic factors that contribute to the leukaemic process in Down's syndrome and in childhood cancer in general. This has already provoked discussion amongst scientists about the chances of identifying a risk group amongst all children that can prevent them from developing leukaemia.
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