Genetic development of immune system linked to leukemia

Scientists have discovered a genetic signature that implicates a key mechanism in the immune system as a driving force for a type of childhood leukemia.

Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia. A key factor driving this leukemia 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 leukemia can fully evolve and prompt symptoms.

Recombination activating gene (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 leukemia. The study was published in Nature Genetics (2014; doi:10.1038/ng.2874).

"For the first time, we see the combined events that are driving this treatable but highly devastating disease," said Elli Papaemmanuil, PhD, from the Wellcome Trust Sanger Institute, in Hinxton, United Kingdom. "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 leukemia."

When the team sequenced the genomes of 57 ALL patients with the fusion gene, they 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 direct them to antibody regions. The team found that remnants of this unique sequence lay close to more than 50% of the cancer-driving genetic rearrangements. Importantly, this process often led to the loss of the very genes required for control of normal immune cell development.

It is the deletion of these genes that, in combination with the fusion gene, leads to the leukemia. This striking genetic signature linking the RAG proteins to genomic instability is not found in other common cancers or other types of leukemia.

"As we sequence more and more cancer genomes, we are increasingly understanding the mutational processes that underpin cancer's evolution," said Peter Campbell, MD, PhD, also of the Sanger Institute. "In this childhood leukemia, we see that the very process required to make normal antibodies is co-opted by the leukemia cells to knock-out other genes with unprecedented specificity."

"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, from The Institute of Cancer Research in London. "But this only happens because the fusion gene (ETV6-RUNX1) that initiates the disease 'traps' cells in a normally very transient window of cell development where the RAG enzymes are active, teasing out their imperfect specificity."

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