Gene defect prior to birth linked to onset of childhood leukemia

A team of researchers has discovered a genetic signature that implicates a key mechanism in the immune system as a driving force for a type of childhood leukaemia.

A key factor driving the leukaemia for one in four ALL patients is a mutation that causes two of their genes, ETV6 and RUNX1, to fuse together. This genomic alteration happens before birth and kick starts the disease.

However, on its own the fusion gene cannot cause cancer; it requires additional mutations before the leukaemia can fully evolve and prompt symptoms.

The new study exploring how this process occurs was carried out by researchers from the Wellcome Trust Sanger Institute and The Institute of Cancer Research, London.

RAG proteins rearrange the genome in normal immune cells in order to generate antibody diversity. In ALL patients with the fusion gene, the team showed that these proteins can also rearrange the DNA of genes involved in cancer, leading to the development of leukaemia.

"We now have a better understanding of the natural history of this disease and the critical events from the initial acquisition of the fusion ETV6-RUNX1 to the sequential acquisition of RAG-mediated genome alterations that ultimately result in this childhood leukaemia," first author from the Wellcome Trust Sanger Institute, Dr Elli Papaemmanuil, said.

To better understand the genetic events that led up to the development of this cancer, the team used single-cell genomics, a state-of-the-art technique that looks at the DNA from an individual cell.

Using samples from two patients, they were able to show that this cancer-causing process occurs many times and results in a continuous diversification of the leukaemia.