Single DNA mutation disrupts tumor suppressor pathways in blood cancer

Australian researchers have discovered that a single mutation in the DNA sequence for a methylation enzyme dysregulates key tumor-suppressing pathways, opening up new avenues for blood cancer treatment. 

The findings of this research confirm mutant DNA methyltransferase 3A (DNMT3A) as a potential target for effective blood cancer treatment. 

One of the most common DNA mutations found in blood cancers is in the sequence encoding DNMT3A. Between 20 and 25% of adults with acute myeloid leukaemia (AML) have mutant DNMT3A. This enzyme travels along DNA and uses methylation to mark which genes should be expressed or silenced. 

Researchers at the Olivia Newton-John Cancer Research Institute (ONJCRI) and WEHI created pre-clinical models with the specific DNMT3A mutation commonly found in human blood cancers. 

From these models, they determined that this mutation hinders DNMT3A's ability to conduct the methylation process. This leads to a cascade of cellular signalling pathways going wrong, which can push blood-forming stem cells toward becoming 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 tumor-suppressor signalling pathway is silenced in cells with DNMT3A mutations, which in turn increases the likelihood that these cells will accumulate additional cancer-causing mutations." 

The researchers used CRISPR-Cas, a genetic engineering technology, to introduce the specific DNA mutation in DNMT3A. Co-lead author and PhD candidate Amali Cooray said: 

"It's not a smoking gun. In the DNA encoding DNMT3A, it's a single base pair that changes. And 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 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 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." 

In 2021, nearly 150,000 people were living with AML worldwide.

This work was funded by NHMRC, a jointly funded PhD scholarship from the Australian Rotary Health District 9650 and The Walter and Eliza Hall Institute, and WEHI, Phenomics Australia, the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program, and the Victorian State Government.