Scientists have discovered a genetic signature that implicates a key mechanism in the immune system as a driving force for a type of childhood leukaemia.
Acute lymphoblastic leukaemia or ALL is the most common form of childhood leukaemia. A key factor driving this 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. But 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, with funding from the Kay Kendall Leukaemia Fund, Leukaemia and Lymphoma Research and the Wellcome Trust.
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.
"For the first time, we see the combined events that are driving this treatable but highly devastating disease," says Dr Elli Papaemmanuil, first author from the Wellcome Trust Sanger Institute. "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."
The team sequenced the genomes of 57 ALL patients with the fusion gene and found that genomic rearrangement and specifically deletions of DNA segments were the predominant drivers of the cancer. All samples showed evidence of events involving the RAG proteins.
The RAG proteins use a unique sequence of DNA letters as a signpost to
|Contact: Aileen Sheehy|
Wellcome Trust Sanger Institute