An established theory of childhood leukaemia development proposes that the immune systems of children who are not exposed to the normal range of early childhood illnesses respond differently when faced with an infection in later years, increasing their risk of developing leukaemia. Dr Williams will examine the mechanisms that may underlie this abnormal reaction.
Testing the role played by infectious exposure in childhood leukaemia development
Dr Owen Williams
UCL Institute of Child Health
London, WC1N 1EH
1 October 2012
Many children diagnosed with leukaemia have a single genetic abnormality in common. However, since this abnormality is also found in healthy people, it is clear that it cannot cause leukaemia on its own.
One theory suggests that the immune systems of children who are not exposed to the normal range of illnesses and infections in early childhood respond differently when faced with an infection in later years. This may trigger blood cells carrying the genetic abnormality to become leukaemic.
Dr Williams will test this theory in the laboratory and will examine how such an immune response may alter the biology of the abnormal blood cells and cause leukaemia.
Leukaemia is the most common form of childhood cancer, affecting up to 500 children (aged 0 – 14 years) every year in the UK.
The genetic abnormalities that underlie the development of childhood leukaemia are thought to arise in utero, leading to the development of pre-leukaemic cells. In most cases these cells are harmless but in rare cases, these pre-leukaemic cells acquire secondary mutations and progress to acute leukaemia.
There is a large body of epidemiological evidence indicating that a child’s risk of developing leukaemia may be associated with their pattern of exposure to infectious disease, with children more exposed to infectious disease in the first few years of life generally being shown to have a reduced risk of developing leukaemia.
To date, however, there is no direct experimental evidence of this association and Dr Owen Williams and colleagues are setting out to produce this evidence in this important laboratory study.
This is an important piece of work as it will permit a better understanding of triggers leading to the formation of childhood leukaemia.
[It] will for the first time be able to directly test this potential connection between infection and development of leukaemia.The normal immune response to infection is mobilised and controlled by production of soluble factors in the blood. The balance between these factors is crucial to the coordinated action of the various components of the immune system and to resolution of the immune response. Delayed childhood infections can lead to abnormal immune responses and a disruption of this balance.
Dr Owen Williams and colleagues will study two abnormal genes known to be associated with childhood ALL – TEL-AML1 and BCR-ABL – using blood stem cells from both mouse and human.
They will examine the effect of a dysregulated immune response on blood cells containing the TEL-AML1 or BCR-ABL cancer genes by exposing the cells to different mixtures of the soluble immune response factors in the laboratory. This will identify combinations of factors that cause enhanced growth of the abnormal blood cells.
They will then examine whether growing the cells containing these cancer genes in the presence of the identified factor combination for long periods of time, will result in changes in the biology of the cells and their molecular makeup, consistent with transformation of the cells into leukaemia.
If the applicants succeed in their goals, it will be a major step forward in our understanding of how leukaemia actually arises.
The team will also analyse molecularly the effect of the TEL-AML1 cancer gene on the response of the abnormal cells to immune response factors, in order to understand how the two interact and predispose to leukaemia formation.
If the team is successful in the work they plan to carry out, this project will provide, for the first time, direct experimental evidence about the role played by infectious exposure in the development of childhood leukaemia. This could have important public health implications.
Dr Owen Williams, UCL Institute of Child Health; Prof Tariq Enver, UCL Cancer Institute; Dr Nicholas Goulden, Great Ormond Street Hospital for Children.