A single nucleotide polymorphism (SNP) in the ARID5B gene has been identified as a risk factor in the most common form of childhood leukaemia. The research, published in Nature Communications, may also suggest the biological mechanisms behind the development of the disease.

Acute Lymphoblastic Leukaemia (ALL) is a very rare disease, being diagnosed in around 650 people in the UK each year. However, about 85% of these cases occur in children under the age of 15 (mostly between 2 and 5 years old), making it the most common form of childhood leukaemia. As with many other forms of leukaemia, ALL affects the production of healthy white blood cells (WBCs) by causing overproduction of immature cells that leave the bone marrow before they are fully formed. Of the 650 cases, 20-25% are characterised by high-hyperdiploidy whereby the cancerous cells possess 51-67 chromosomes. The condition is therefore known as high-hyperdiploid ALL (HD-ALL).

This study, performed by researchers at the Institute of Cancer Research (ICR) in London in collaboration with Lund University in Sweden, focused on a region of DNA which has previously been implicated in HD-ALL. Using fine mapping and epigenetic profiling, the team were able to identify a single nucleotide variant (commonly known as a SNP) within the ARID5B gene that was linked to an increased risk of developing ALL. A healthy ARID5B gene is involved in the successful production of functioning WBCs. When the SNP was present, the results showed that expression of ARID5B was greatly reduced and WBC production was significantly hindered.

When focusing on HD-ALL, the team also discovered that a large proportion of cases displayed at least 1 extra copy of the variant, further hindering gene expression.

By studying how reduced expression affected WBC development, the team theorised that the SNP was interfering with the way DNA is ‘unpacked’ in young WBCs. Changes to the natural mechanism present in healthy cells led to immature cancerous cells, known as blasts, being released into the bloodstream before their development was completed.

Leukaemia cases are more treatable when discovered earlier. By improving our understanding of how the diseases develop, we may be able to design diagnostic systems that can identify high risk patients and give them access to treatment at an earlier stage of development.

“This study expands our understanding of how genetic risk factors can influence the development of acute lymphoblastic leukaemia, which is the most common form of childhood leukaemia,” said Richard Houlston, Ph.D., M.D., Professor of Molecular and Population Genetics at the ICR. “We implicate reduced expression of a gene called ARID5B in the production and release of the immature ‘blast’ cells that characterise the disease, and in particular in the development of a form called high-hyperdiploid leukaemia. Our study gives a new insight into the causes of the disease, and may open up new strategies for prevention.”

The research was funded by the UK-based charity Bloodwise, with additional support from Cancer Research UK and the Swedish Childhood Cancer Foundation.

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