Infection-fighting cellular process 'a cause of childhood leukemia'
The American Cancer Society states that leukemia is the most common cancer in children and teens in the US, accounting for 1 in 3 cancers. Now, researchers have found that a cellular mechanism that fights off infection may contribute to the development of the disease in youngsters, opening doors for further research into treatment for the condition.
According to the study researchers from the Wellcome Trust Sanger Institute and The Institute of Cancer Research, both in the UK, 1 in 4 children develop ALL as a result of a gene mutation prior to birth. The mutation is caused by two genes - ETV6 and RUNX1 - fusing together.
However, the investigators note that this "fusion gene" needs to go through additional mutations before leukemia can fully develop.
Fusion gene 'rearranges' DNA of cancer genes
For their study, the research team wanted to investigate how this process worked. They analyzed and sequenced the genomes of 57 patients with ALL who had the fusion gene.
In normal immune cells, the researchers explain that genes that fuse together - known as recombination activating gene (RAG) proteins - rearrange the genome as a way of creating a good mix of antibodies.
But in ALL patients with the fusion gene, they found that the RAG proteins are also able to reorganize the DNA of genes that play a part in cancer, triggering the development of leukemia.
In detail, the investigators explain that the RAG proteins use an exclusive DNA letter sequence as a marker to lead them to antibody regions.
They discovered that the remains of the DNA letter sequence settle significantly close to over 50% of cancer-driving genes, and that the rearrangement process often causes genes needed for regulation of normal immune cell development to be lost.
The researchers say their findings show that the combination of the fusion genes and the loss of genes required for normal immune cell development cause leukemia.
Potential for 'improved diagnostics and targeted therapy'
Commenting on their findings, Dr. Elli Papaemmanuil, of the Wellcome Trust Sanger Institute and first author of the study, says:
"For the first time, we see the combined events that are driving this treatable but highly devastating disease.
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."
Further investigation using single-celled genomics - analysis of DNA from an individual cell - in samples from two ALL patients with the gene fusion revealed that the RAG protein rearrangement process happens multiple times, which causes a "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," says Prof. Mel Greaves, of The Institute of Cancer Research and co-senior author of the study.
"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."
The investigators say they now plan to determine how "RAG-mediated genomic instability" builds up in cells with the gene fusion, and to find out how this process works in patients with recurrent leukemia.
Dr. Peter Campbell, of the Wellcome Trust Sanger Institute and co-author of the study, adds:
"The more we understand about the genetic events that underlie leukemia and other cancers, the better equipped we are to develop improved diagnostics and targeted therapy for patients with this disease."
In September last year, Medical News Today reported on a gene study showing that both susceptibility and survival of childhood leukemia can be inherited.
Written by Honor Whiteman
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