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Scientists have discovered a genetic signature that implicates a key mechanism in our immune system as a driving force behind Acute lymphoblastic leukaemia (ALL) the most common form of childhood leukaemia.
A key factor driving ALL leukaemia for one in four ALL patients is a mutation causing two of the victim's genes — ETV6 and RUNX1 — to fuse together. This genomic alteration happens before birth and kick starts the disease.
On its own the fused gene cannot cause cancer; it requires additional mutations before the leukaemia fully evolves.
This new study explores how this process occurs and 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. Their work is published in Nature Genetics 12 Jan., 2014 DOI: 10.1038/ng.2874
Recombination activating genes (RAGs) encode enzyme proteins which rearrange the genome in normal immune cells to generate antibody diversity. In ALL patients with the ETV6 and RUNX1 fusion gene, researchers reveal how the proteins generated by this fusion can lead to the development of leukaemia.
The team sequenced the genomes of 57 ALL patients with the fusion gene and found that genomic rearrangement with specific deletions of DNA segments, are the predominant drivers of ALL cancer. All samples showed evidence of events involving RAG proteins.
"As we sequence more and more cancer genomes, we increasingly understand the mutation processes that support cancer's evolution," says Dr Peter Campbell, co-lead author from the Wellcome Trust Sanger Institute. "In ALL childhood leukaemia, we see the process required to make normal antibodies is co-opted by leukaemic cells which knock-out other genes specific for a normal immune response."
To better understand the genetic events that led up to the ALL cancer, the team used single-cell genomics, a state-of-the-art technique that can monitor DNA from an individual cell. Using blood samples from two patients, researchers followed the process which resulted in the DNA fusion and protein diversification leading to leukaemia.
"It may seem surprising that evolution should have provided a mechanism for diversifying antibodies that can collaterally damage genes that then contribute to cancer," said Professor Mel Greaves, co-senior author of the study from The Institute of Cancer Research, London, "But this only happens because the fusion gene (ETV6-RUNX1) that initiates the ALL disease 'traps' cells in a normally very transient period of cell development when RAG enzymes are active, allowing their imperfect specificity to become manifest."
"The more we understand about the genetic events that underlie leukaemia and other cancers, the better equipped we are to develop improved diagnostics and targeted therapy for patients with this disease," adds Dr Campbell.
Leukaemia & Lymphoma Research is the only UK charity dedicated to improving the lives of patients with all types of blood cancer, including leukaemia, lymphoma and myeloma. Its life-saving research is focused on finding causes, improving diagnosis and treatments, and running ground-breaking clinical trials for all blood cancer patients. Around 30,000 people of all ages, from children to adults, are diagnosed with blood cancers every year in the UK. http://www.beatingbloodcancers.org.uk
The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www.sanger.ac.uk
The Institute of Cancer Research, London, is one of the world's most influential cancer research institutes.
Scientists and clinicians at The Institute of Cancer Research (ICR) are working every day to make a real impact on cancer patients' lives. Through its unique partnership with The Royal Marsden NHS Foundation Trust and 'bench-to-bedside' approach, the ICR is able to create and deliver results in a way that other institutions cannot. Together the two organisations are rated in the top four cancer centres globally.
The ICR has an outstanding record of achievement dating back more than 100 years. It provided the first convincing evidence that DNA damage is the basic cause of cancer, laying the foundation for the now universally accepted idea that cancer is a genetic disease. Today it leads the world at isolating cancer-related genes and discovering new targeted drugs for personalised cancer treatment.
As a college of the University of London, the ICR provides postgraduate higher education of international distinction. It has charitable status and relies on support from partner organisations, charities and the general public.
The ICR's mission is to make the discoveries that defeat cancer. For more information visit http://www.icr.ac.uk.
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests. http://www.wellcome.ac.uk