A new study has revealed that two of the most common mutations found in an age-related blood condition may be associated with inflammation through distinct biological pathways.
The study, published in GeroScience, investigated DNMT3A and TET2, the two most common mutations in clonal haematopoiesis, an age-related condition in which mutated blood stem cells expand and form larger populations of blood cells.
Researchers found that large DNMT3A-mutant clones showed widespread reactivation of normally suppressed retrotransposable elements - parts of the 'dark genome' that include remnants of ancient viral sequences. In contrast, TET2 showed lower activity in the dark genome but changes in pathways associated with cellular metabolism and oxidative stress.
Our findings suggest that inflammation associated with clonal haematopoiesis may arise through different biological mechanisms depending on the mutation involved. Understanding these differences could help us identify new biomarkers for people at greater risk of developing associated diseases, including cardiovascular disease and blood cancers."
Lead author Dr Mohammad Mahdi Karimi, Senior Lecturer in Bioinformatics, King's College London
He added: "In the future, we hope to establish whether targeting these specific inflammatory pathways could provide new ways to prevent or treat disease in people with clonal haematopoiesis."
Clonal haematopoiesis occurs when a mutation in a haematopoietic stem cell results in the expansion of a population of blood cells carrying the same mutation. It is associated with adverse health outcomes, including blood cancers, cardiovascular disease and atrial fibrillation, where the heartbeat is irregular or abnormally fast.
DNMT3A and TET2 both help regulate which parts of our DNA are active or suppressed. The researchers therefore investigated whether mutations in these genes could affect the activity of transposable elements - stretches of DNA that are normally kept switched off.
More than 40% of the human genome, called the 'dark genome', consists of repetitive genetic elements known as transposable elements, including a major group called retrotransposable elements (RTEs). These include remnants of ancient viruses that became embedded in our ancestors' DNA millions of years ago. These sequences are normally kept tightly suppressed, including through a process called DNA methylation.
In this study, the researchers analysed blood samples from 68 people, with 56 having CH and 12 acting as non-CH controls. The participants were all over 50 and undergoing hip replacement surgery.
They focused on two of the most common mutations found in clonal haematopoiesis - DNMT3A and TET2 - to understand why these mutations cause inflammatory changes.
DNMT3A is an enzyme involved in controlling DNA methylation. If a blood stem cell acquires a damaging DNMT3A mutation, this system can become disrupted. The researchers found evidence that this is associated with RTEs becoming activated, particularly when the population of blood cells carrying the mutation was large. This reactivation was associated with inflammatory pathways, including TNF-NFκB and interferon signalling.
In contrast, TET2-mutant cells showed lower levels of retrotransposable-element activity and lacked the same dark-genome-associated inflammatory signatures. Instead, they showed changes in pathways associated with cellular metabolism and oxidative stress, suggesting inflammation may arise through a different mechanism.
The findings therefore indicate that although both mutations are associated with inflammation, the underlying biological processes may be different.
The researchers believe that RTE activation could eventually be used as a biomarker. If future experiments demonstrate that RTE activation directly contributes to inflammation, targeting this pathway could also potentially provide a new approach to treatment.
This study was funded by Celgene, a Bristol Myers Squibb company through a partnership with King's Health Partners.
