Antibody machinery linked to childhood leukaemia
The cell machinery that helps fight off infection could be a driving force behind the most common form of childhood leukaemia, UK scientists have found.
“This exciting piece of research demonstrates how a normal cellular process required to develop a functional immune system could also drive genetic changes that fuel the most common form of childhood leukaemia." - Professor Josef Vormoor, Cancer Research UK
The tools behind the ‘genetic reshuffling’ that helps the immune system produce millions of antibodies could also be responsible for genetic changes that drive acute lymphoblastic leukaemia (ALL).
Researchers from the Wellcome Trust Sanger Institute and The Institute of Cancer Research found that important molecules – called the RAG enzymes – that help rearrange DNA in normal immune cells could also rearrange genes linked to cancer.
Publishing their findings in the journal Nature Genetics, the scientists focussed on patients with an important genetic ‘fingerprint’ for ALL.
The fusion of two genes called ETV6 and RUNX1 before birth can kick-start the development of ALL in around a quarter of patients, but does not cause the disease on its own.
The researchers sequenced the genomes of 57 ALL patients who carry the fusion fingerprint. They found that the combination of the fusion gene and DNA rearrangements caused by the RAG enzymes drives this form of leukaemia.
Dr Elli Papaemmanuil, from the Wellcome Trust Sanger Institute and an author of the study, said the research provides a better understanding of the "critical events" that result in ALL.
Dr Papaemmanuil added: "For the first time, we see the combined events that are driving this treatable but highly devastating disease."
Professor Josef Vormoor, a Cancer Research UK expert in leukaemia, said: “This exciting piece of research demonstrates how a normal cellular process required to develop a functional immune system could also drive genetic changes that fuel the most common form of childhood leukaemia.
“By reshuffling DNA regions, the RAG enzymes provide vital genetic diversity that allows the immune system to distinguish our own cells from invading microbes, bacteria and viruses. This research offers compelling evidence for a trade off between useful diversity of the immune system and harmful genetic changes that could contribute to leukaemia.
“The next steps will be to see if this mechanism applies to other forms of leukaemia and find out whether the genetic changes reported in this study could be responsible for treatment resistance seen in some patients.”
- Papaemmanuil E, et al. (2014). RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia, Nature Genetics, advance online publication 1546-1718. DOI: 10.1038/ng.2874