A new approach to investigating the cause of childrens leukaemia.

Dr Ian N. Hampson & Dr Lynne Hampson

University of Manchester Viral Oncology Labs., St Mary's Hospital, Oxford Road,  Manchester M13 OJH

Tel 01617016938 e-mail ian.hampson@manchester.ac.uk

In the UK approximately 500 children are diagnosed with leukaemia every year which makes this the most common childrens cancer with roughly 80% of these being of the type called acute lymphoblastic leukaemia (ALL). Although in recent years cure rates for ALL have increased dramatically, current treatments are debilitating with the very real possibility of long-term therapy related complications.

Animals also get leukaemia and it is known that most of these are caused by infections with specific types of virus. However, in spite of indirect evidence for chidrens ALL also being caused by an infectious agent, none have been identified so far. Curiously in adults there is a virus called human T-cell leukaemia virus type 1 (HTLV-1) which, as the name implies, causes T-cell leukaemia in adults yet no such virus has been found which causes childrens disease. Although HTLV-1 is known to be endemic in some countries such as Japan, the Caribbean, parts of Africa and South America it is not very common in the UK (0.001% in blood donors).

Why is it so difficult to find an unknown virus which may be causing childrens ALL? One problem is that this type of virus does not usually cause acute symptoms and will most often go undetected. Furthermore, viruses can infect, cause damage but are then cleared by the immune response. If ALL subsequently develops from the damage caused by the virus, the virus can be long-gone by the time the leukaemia emerges. This is the, so called, “Hit and Run” hypothesis.  Another very significant difficulty is that a very high proportion of human DNA (8%) is made up of virus-like sequences which are of the same type of virus as HTLV-1. Basically, you can’t see the wood for the trees! So how can we address these problems?

In order to appreciate how, it is necessary to understand how the human genome was first sequenced in the past and, most importantly, how it can be done today. The first draft of the human genome published in 2003 took approximately 13 years to complete, involved the work of hundreds of scientists and machines and cost approximately 3 billion US dollars. Using the new technology of “Next Generation” DNA sequencing it has just been announced this can now be achieved with one operator plus a single machine in less than a day and the cost is predicted to be less then $1000 by the end of 2012.

When challenged by an infectious agent, humans produce antibodies which are specific for the particular type of infection and it is estimated that one individual can generate roughly 10 billion different antibodies. These antibodies then persist as an immunological memory of both current and past infections. We intend to combine traditional methods of molecular biology with the new “Next Generation” sequencing technology to compare the antibody repertoires of children who have ALL with that of normal control children. The output will be the identity of any present or past infections detected in children with ALL that are not in normal controls. It is only by harnessing the awesome power of this new sequencing technology that it has now become possible to compare the complex mixture of antibody repertoires from different groups of people.

What is the potential benefit for children with this disease? If specific infections can be identified which are linked to childhood ALL, ultimately, it may be possible to introduce vaccine based approaches for prevention and, for cancer, prevention is definitely better than the cure! The valuable support provided by the CCT will enable us start this project in the near future and we thank all the trustees and supporters for their help.