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expert reaction to review looking at possible causes and triggers of acute lymphoblastic childhood leukaemia

A new analysis, published in Nature Reviews Cancer, shows the likely causes of most cases of childhood leukaemia.

A briefing accompanied this roundup.

 

Dr Donna Lancaster, Consultant Paediatric Oncologist at The Royal Marsden NHS Foundation Trust, said:

“Leukaemia is one of the most common types of cancer occurring in childhood with approximately 500 cases in the UK each year.  There are two types: Acute Lymphoblastic Leukaemia (ALL) and Acute Myeloid Leukaemia (AML).  ALL is the most common type, with the highest incidence in children aged 0 to 4 years.  It commonly presents with fatigue, bruising, general aches and infections.

“There are a number of theories as to the cause but it is thought that genetic changes occur in the cells in the bone marrow before birth and a subsequent infection may trigger changes which give rise to leukaemia.  There is no proven link yet with a specific infection.  Children with Down’s syndrome have a higher incidence of leukaemia and identical twins where one child is affected but the there is no increased risk in siblings.

“The treatment of childhood leukaemia is now very successful with more than 90 per cent of children with ALL and 70 per cent with AML surviving in to adulthood.  The Royal Marsden is pioneering new more targeted therapies in collaboration with other centres in the UK and Europe which we hope will improve the outcome for those children who don’t respond to conventional treatment.

“This new study suggests that early exposure to infection may be beneficial in some children with a genetic predisposition to childhood leukaemia.  However, this still needs further investigation and any exposure of young children to infection has to be balanced with the risk of the infection.  In the future, there may be ways to develop an immunisation which mimics this process in order to prevent leukaemia from developing.”

 

Dr Alasdair Rankin, Director of Research at the blood cancer charity Bloodwise, said:

“Decades of research by Professor Greaves have shown that the most common type of childhood leukaemia is most probably caused by an abnormal response to infection in children already at risk.

“Current treatments for childhood leukaemia are not always successful, and even when they are, can have severe short and long-term side effects, so research to find kinder treatments is very important.  If we could stop this type of leukaemia from happening in the first place it would be enormously exciting, but many more questions still need to be answered in the research lab before we will know for sure whether that could become a reality.

“We urge parents not to be alarmed by this study – childhood leukaemia is very rare and only around one in 2,000 children will develop it.  While developing a strong immune system early in life may slightly further reduce risk, there is nothing that can be currently done to definitively prevent childhood leukaemia.  As noted by this study, other factors influence its development – including pure chance.”

 

Prof Chris Bunce, Professor of Translational Cancer Biology, University of Birmingham, said:

“Mel Greaves is one of the superstars amongst modern cancer biologists.  For most of his career he has been working on understanding the biology of childhood leukaemias and how they arise.  His work has been instrumental in demonstrating that the initial mutation for many if not all childhood leukaemias occurs in a cell in the unborn child.  He and others have also shown that it’s a minority of individuals who receive such a hit that go on to get actual leukaemia and therefore some other activating event must occur after birth.

“In this comprehensive review of his own work and that of many others Prof Greaves focuses on one subtype of leukaemia called B cell precursor childhood acute lymphoblastic leukaemia (BCP-ALL) and provides the argument that early exposures to common infections protect from the disease whereas diminished exposure to infections early in life increases the risks of later infections promoting BCP-ALL.  This understanding of the origins of the disease provide insight to possible future strategies for leukaemia prevention.

“In this review Prof Greaves brings together epidemiological, sociological, immunological, genetic and cellular information to piece together a compelling model of how a blood cancer called B cell precursor childhood acute lymphoblastic leukaemia (BCP-ALL) arises in children.

“Prof Greaves argues that the rise in incidence of B cell precursor childhood acute lymphoblastic leukaemia in developed societies may be an unforeseen consequence of our cleaner living.  He argues that exposure to infectious agents early in life protect against the disease whereas delayed exposure to infections can promote the diseases development.”

 

Prof Charles Swanton FRS, Cancer Research UK’s chief clinician, said:

“This research sheds light on how a form of childhood blood cancer might develop, implicating a complex combination of genetics and early exposure to germs, dirt, and illness.  But it’s important to emphasise that less than one per cent of children who have the genetic predisposition described in this review, go on to develop acute lymphoblastic leukaemia (ALL).  Childhood leukaemia is rare and it’s currently not known what or if there is anything that can be done to prevent it by either medical professionals or parents.  We want to assure any parents of a child who has or has had leukaemia, that there’s nothing that we know of that could have been done to prevent their illness.”

 

Prof Sheena Cruickshank, British Society for Immunology spokesperson and Professor of Public Engagement and Biomedical Sciences at The University of Manchester, said:

“This is an interesting review which has collated evidence from a large collection of papers to support the author’s view that very young childhood infection exposure may be protective to acute lymphoblastic leukaemia (ALL) whereas later exposure may be harmful where there has not been an earlier infection history.

“The immune response and its regulation are crucial for our well-being, and defects in immune function are associated with a number of conditions, including autoimmunity and allergy.  However, from the evidence presented in this review, it’s not yet clear what role infection-induced inflammation, or even inflammation, will have in the development of ALL and much more investigation is needed to better define the role of the immune system or infectious agents in the development of this disease.

“It’s also important to remember that infections themselves can pose a significant risk for young babies with a developing immune system.  Parents should not be unduly alarmed by this review.  ALL is a rare disease, and there are likely to be many different factors involved in its development.”

 

Prof Shirley Hodgson, Professor of Cancer Genetics, St George’s, University of London, said:

“The work of Prof Mel Greaves regarding the aetiology of childhood leukaemia is well known and he has an established record in this field.  His theory is that childhood acute lymphoblastic leukaemia (ALL) is caused by two sequential mutations (genetic alterations caused by translocations) in the blood of children, the first occurring in foetal life and the second in early childhood.  Only a small proportion of children with the first priming mutation (about 1%) develop ALL.

“The first mutation causes a clone of cells that can survive in the blood for years but which in itself does not cause disease.  The evidence for the priming mutation is good, for instance shown by the fact that when the first mutation occurs in an identical twin foetus, it can be transferred to the other identical twin through linked blood supplies, and detected in the children’s blood.  ALL develops in one or both twins in childhood only after a second mutation occurs in the affected twin.

“The second mutation has been shown to occur as a result of viral infections in childhood.  This is more likely to develop in children who have been raised in a ‘clean environment’ as toddlers, leaving them unexposed to virus infections at a crucial stage in their immune system development.  The suggestion is that the immune system requires to be programmed by exposure to viruses in the early years of life.

“The evidence for this theory is wide-ranging, from epidemiological (observed leukaemia clusters in areas exposed to viral infections, and reduced leukaemia risk in children who were breast fed and in those who attended playgroups as toddlers), to experimental / molecular in man (evidence of viral infections in clustered cases of ALL in man, and persuasive evidence for the two hit hypothesis in mice).

“The message for the future is that it may be possible to prevent ALL by exposing infants to benign viral infections, for instance by immunisation.  This theory also makes it unnecessary to postulate other causative theories for ALL such as exposure to electromagnetic waves.”

 

* ‘A causal mechanism for childhood acute lymphoblastic leukaemia’ by Mel Greaves will be published in Nature Reviews Cancer on Monday 21 May 2018. 

 

Declared interests

Dr Alasdair Rankin: “Bloodwise have funded research projects by Prof Greaves for many years, many of which are referenced in this Nature Reviews Cancer paper.”

Prof Chris Bunce: “No conflicts of interest.  In 2012-15 I was Research Director at Bloodwise – Mel recognises Bloodwise for their funding in his acknowledgments in the paper.”

Prof Shirley Hodgson: “I confirm that I have no conflicts of interest.”

None others received.

 

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