a patient with ALL
Investigators have identified the genetic events leading to leukemic transformation in ETV6-RUNX1 acute lymphoblastic leukemia (ALL), according to a paper published in Nature Genetics.
Previous studies have shown that, for 1 in 4 ALL patients, a key factor driving the disease is a chromosomal translocation that creates the ETV6-RUNX1 fusion gene.
However, the gene cannot cause overt leukemia on its own. Additional mutations are required for ALL to develop.
In this study, researchers found that RAG proteins—which rearrange the genome in normal immune cells to generate antibody diversity—can also rearrange the DNA of genes involved in cancer.
And this leads to ALL in individuals with the ETV6-RUNX1 fusion gene.
“For the first time, we see the combined events that are driving this treatable but highly devastating disease,” said lead study author Elli Papaemmanuil, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.
“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.”
To unearth this discovery, the investigators sequenced the genomes of 57 ALL patients with the fusion gene. The team found that genomic rearrangements, and deletions in particular, were the predominant drivers of leukemia.
All samples showed evidence of events involving the RAG proteins. The proteins use a unique sequence of DNA letters as a signpost to direct them to antibody regions.
The researchers discovered that remnants of this sequence lay close to more than 50% of the cancer-driving genetic rearrangements. And this process often prompted the loss of the very genes required for normal immune cell development.
It is the deletion of these genes that, in combination with the fusion gene, leads to ALL, the investigators said. And the genetic signature linking the RAG proteins to genomic instability is not found in other types of leukemia or other common cancers.
“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,” said Peter Campbell, PhD, also of the Wellcome Trust Sanger Institute.
To better understand the events that led to ALL development, the researchers used single-cell genomics to analyze samples from 2 patients. The team found that the cancer-causing process they identified occurs many times and results in continuous diversification of the leukemia.
“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 Mel Greaves, PhD, of The Institute of Cancer Research in London, UK.
“But this only happens because the fusion gene 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.”
The researchers are now planning to investigate how the RAG-mediated genomic instability accrues in cells with the ETV6-RUNX1 fusion gene and what role this process plays in patients who relapse.
