Analysis: studies suggest that the cause of leukaemia is due to a combination of genetic mutations and exposure to infection
Leukaemia is a type of blood cancer that affects both white blood cells, the key players in the body's defence against infection, and bone marrow, the spongy soft centre of the bone where blood cells are made. In leukaemia, these white blood cells become abnormal and are unable to mature. They begin to accumulate in the bone marrow, eventually building up to a stage where they spill out into the bloodstream.
There are two main types of leukaemia: acute, or fast-growing leukaemia, and chronic, or more slow-growing leukaemia. These two main types can be further subdivided depending on the type of blood cell that the leukaemia affects. For example, acute myeloid leukaemia (AML) affects cells from the myeloid background, but acute lymphocytic leukaemia (ALL) affects those from the lymphoid lineage.
Childhood leukaemia tends to be nearly always acute, with this type representing the most common cancer in children. Within this, ALL is the most common, accounting for more than a quarter of childhood cancers. AML represents 15% of childhood leukaemias and 5% of childhood cancers. The 5 year survival rate (the percentage of patients that live for at least 5 years after their cancer has been diagnosed), has improved over time for ALL and is now at 91%. In contrast, the 5-year survival rate for all subtypes of AML is only 66%. In addition, the treatment that the patient undergoes is traumatic, toxic and has long term side-effects associated with it.
From Cancer Research UK, Katrin Ottersbach from the University of Edinburgh on understanding childhood leukaemia
Childhood leukaemia is a complex disease with the exact cause of it being unknown in most patients. Children who develop leukaemia often have no known risk factors associated with the disease. Despite this, significant scientific discoveries have been made to define the key genes within leukaemia and to reveal the complexity underlying the development and progression of this disease. Changes to DNA, the chemical inside our cells that makes up our genes and controls how our cells function, can result in our cells losing their ability to function properly. This can cause the cells to grow out of control and become cancerous.
There are several types of DNA changes that can result in a cell becoming cancerous. One of these is known as a chromosome translocation and tends to occur before birth in childhood leukaemia. Chromosomes, of which there are 23 pairs of in humans, are how our cells organise the DNA. When a translocation occurs, DNA from one chromosome breaks off and attaches to another chromosome. In some cases, this translocation is enough to initiate the leukaemia. However, in most cases a postnatal event is required for disease development. For example, the changes to the DNA due to the translocation, can lead to the generation of an oncogene. These are genes that encode for proteins which help the cells to stay alive, grow or divide abnormally, and thus become cancerous.
Fusion genes are a type of oncogene that occur when two genes, that were previously separate, come together to form a new hybrid gene. An example of this in AML is MLL-AF9 rearranged leukaemia, a rearrangement that tends to be more associated with childhood leukaemia. This arises due to a translocation between chromosomes 9 and 11. This translocation then leads to the formation of the MLL-AF9 fusion gene which, when transcribed, produces the MLL-AF9 fusion protein. This protein causes dysregulation in the cell, and can initiate leukaemia development.
The function of the immune system is to fight infection but, in order for our immune system to function properly, it needs to be exposed to infection early on in life
There are other causes of leukaemia, related to genetics, that can increase a child's risk of developing leukaemia. One of the most common is Down's Syndrome. This is where abnormal cell division early on in development produces an extra copy of chromosome 21. These children have extra genetic material leading to developmental changes characteristic of an individual with Down’s Syndrome. Children with Down’s Syndrome are 150 times more likely to develop AML and 33 times more likely to develop ALL.
Other studies conducted suggest that the cause of leukaemia is due to a combination of genetic mutations and exposure to infection. This two-step process, first involves a genetic mutation occurring before birth, predisposing the child to leukaemia. A marginal number of children (only 1%) that are born with this mutation actually go on to develop the disease, showing the importance of the second step in this process for disease development. This mutation is not believed to be inherited and is most likely a developmental accident. The second step involves the exposure of the child to one or more common infections, prompting the initiation of the disease.
Professor Mel Greaves from The Institute of Cancer Research has been researching why children get leukaemia for over 30 years. He believes that "the problem is not infection, but lack of infection early in life". This theory is known as the delayed infection theory and is believed to be the cause of ALL.
The Institute of Cancer Research's Mel Greaves on the likely cause of childhood leukaemia
The function of the immune system is to fight infection but, in order for our immune system to function properly, it needs to be exposed to infection early on in life (this is known as priming of the immune system). It is believed that infection later on in life, without earlier priming, can cause the immune system to malfunction and over-react. This over-reaction involves the production of chemicals, known as cytokines, into our bloodstream, which can then result in the development of leukaemia in children who carry the first mutation.
Although research is ongoing to investigate the cause of leukaemia, the exact cause of childhood leukaemia is currently unknown. Furthermore, there are several different types of leukaemia and each individual’s leukaemia is different so pioneering research to both increase our understanding of childhood leukaemia development and to catalyse the development of new, kinder therapies is necessary..
Rachael Wilson is a MSci (Hons) student Natural Sciences at the University of Bath who is currently on her Placement Year at the Northern Ireland Centre for Stratified Medicine at the School of Biomedical Sciences at Ulster University. Dr Kyle Matchett is a Lecturer in Molecular Immunology at the Northern Ireland Centre for Stratified Medicine at the School of Biomedical Sciences at Ulster University