New research demonstrates how a single DNA mutation affects tumour-prevention mechanisms, increasing the risk of blood cancer
Dr Erin Lawrence, co-lead author, and Amali Cooray, co-lead author and PhD candidate
Researchers at the Olivia Newton-John Cancer Research Institute (ONJCRI) and WEHI have demonstrated how a single DNA mutation disrupts tumour-prevention mechanisms and increases the risk of developing blood cancer, offering new avenues for treatment in the future.
A DNA mutation is a permanent change in the DNA sequence of an organism. One of the most common mutations found in blood cancers affects a gene called DNMT3A. Between 20 and 25% of adults with acute myeloid leukaemia (AML), a type of blood cancer, have mutant DNMT3A.
The researchers have determined that a specific DNA mutation affects DNMT3A’s ability to initiate a mechanism that prevents tumours from forming.
As these cells with mutant DNMT3A are exposed to stressors, their DNA becomes increasingly damaged, which can push them to become cancerous over time.
Dr Erin Lawrence, co-lead author on the paper published in EMBO Reports today, said: “We discovered that cells carrying DNMT3A mutations are less equipped to respond to stress, which can lead to DNA damage. One of the pathways involved in sensing and repairing this DNA damage is the p53 tumour-suppressor pathway.
“We found that the p53 tumour-suppressor pathway is silenced in cells with DNMT3A mutations, which in turn increases the likelihood that these cells will accumulate additional cancer-causing mutations.”
Co-lead author and PhD candidate Amali Cooray said: “It’s not a smoking gun. In the DNA encoding DNMT3A, it’s a single mutation that causes all of these effects downstream.”
Cooray emphasises that not all individuals living with this mutation will go on to develop cancer: “If you look at cohorts over the age of 60 or 70, suddenly the mutation is in 10–20% of people. Plenty of older people have this mutation and are perfectly healthy.”
These new insights could offer new avenues to treat DNMT3A-mutant cancers. Dr Lawrence said: “AML remains stubbornly challenging to treat, and there are currently no targeted therapies for DNMT3A-mutant cancers.”
Professor Marco Herold, CEO of ONJCRI and senior author
Professor Marco Herold, CEO of ONJCRI, Head of the Blood Cancer and Immunotherapy Lab, and senior author of the EMBO Reports paper, said: “For people who have DNMT3A-mutant blood cancers, we might be able to understand exactly how their cancer develops, and that gives us a better chance of developing more effective, targeted therapies that are more tolerable.”
According to the Leukaemia Foundation, more than 135,000 people are living with blood cancer or a related blood disorder in Australia today, with 900 diagnosed with AML each year.
ENDS
This work was funded by NHMRC, a jointly funded PhD scholarship from the Australian Rotary Health District 9650 and WEHI, and the Alfred Hughes PhD Scholarship (WEHI), Phenomics Australia, the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program, and the Victorian State Government