Single DNA Mutation Impairs Tumor Suppressor Pathways, Increasing Blood Cancer Risks

Researchers from the Olivia Newton-John Cancer Research Institute and WEHI have identified a crucial link between a specific DNA mutation and the development of blood cancers. The mutation occurs in the gene encoding the enzyme DNA methyltransferase 3A (DNMT3A), which plays a vital role in regulating gene expression through methylation. In a significant discovery, the scientists found that this mutation hampers DNMT3A's ability to perform its normal function, leading to disruptions in cellular signaling pathways that control blood stem cell behavior.

Approximately 20% to 25% of adults diagnosed with acute myeloid leukemia (AML) harbor mutations in DNMT3A. These mutations result in a single base change in the DNA sequence, which profoundly affects the enzyme's activity. The inability of mutant DNMT3A to properly methylate DNA causes a cascade of cellular effects, notably silencing the p53 tumor-suppressor pathway. The p53 pathway is essential for responding to DNA damage and preventing the proliferation of potentially cancerous cells.

Using CRISPR-Cas gene editing, the research team modeled this specific mutation and observed that cells carrying the mutation are less responsive to stress and accumulate DNA damage. This deficiency in DNA repair mechanisms increases the chances of additional mutations, escalating the risk of cancer progression. Interestingly, while the mutation increases cancer susceptibility, it is also found in a significant portion of healthy older adults without disease, highlighting the complex nature of genetic predisposition.

Dr. Erin Lawrence, co-lead author, emphasized the importance of these findings: "Understanding how a single DNA change can inactivate tumor suppressor pathways opens up new possibilities for targeted therapies. Currently, there are no effective targeted treatments for DNMT3A-mutant blood cancers, but this research provides a promising direction."

The study suggests that targeting the disrupted pathways caused by the mutation could lead to novel treatments and improve outcomes for patients with DNMT3A-associated blood cancers. Ongoing research aims to develop strategies to reverse or compensate for the effects of this mutation, offering hope for more effective therapies in the future.

Source: https://medicalxpress.com/news/2025-04-dna-mutation-disrupts-key-tumor.html