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As individuals progress through life, their blood stem cells—the primary source of new blood cells—can accumulate genetic mutations. These changes may provide the cells with a survival advantage, potentially leading to significant health complications. Recent research conducted by scientists at The Jackson Laboratory (JAX) has uncovered both the mechanism responsible for the unchecked proliferation of these cells and a potential method to halt this process.
The investigation, led by Jennifer Trowbridge, professor and holder of The Dattels Family Chair at JAX, is highlighted in the April 16 issue of Nature Communications. The study reveals that a frequently occurring mutation associated with aging in the Dnmt3a gene enhances the energy-producing abilities of mitochondria within blood stem cells. This mutation enables these cells to replicate more efficiently, creating an environment conducive to clonal hematopoiesis—a condition that significantly heightens the likelihood of developing heart disease, blood cancers, and additional serious illnesses.
Clonal hematopoiesis often progresses without noticeable symptoms as individuals age; it is estimated that over half of individuals at 80 years old are affected. Despite being asymptomatic, the mutated blood stem cells involved in this condition produce inflammatory substances that can disrupt normal blood production and compromise immune system function.
“This research opens up a new perspective on how and why blood stem cells evolve with age, and this ultimately increases the risk for diseases such as cancer, diabetes, and cardiovascular issues,” Trowbridge explained. “It also suggests a potential avenue for intervention that could help prevent age-related diseases, not just within the blood but in any area impacted by blood.”
A prevalent genetic alteration
Building upon her earlier findings and related research, Trowbridge’s team recognized that Dnmt3a mutations are commonly observed in aging blood stem cells, as well as various forms of blood cancers. To uncover why these mutated cells have a competitive edge over their unaltered counterparts, the researchers created a mouse model harboring the Dnmt3a mutation.
The results of their study revealed that middle-aged mice with these mutations exhibited double the energy production capabilities compared to normal cells, along with significantly enhanced mitochondrial function—granting these mutated stem cells a notable growth advantage.
“This was quite surprising,” Trowbridge remarked. “The influence of this gene on metabolic processes and mitochondrial behavior was not previously understood.”
Focusing on mitochondria
The research team recognized that since the stem cells with Dnmt3a mutations relied extensively on their hyperactive mitochondria for growth, these cellular powerhouses represented a potential vulnerability. They evaluated the impact of MitoQ and d-TPP—compounds that disrupt standard mitochondrial functioning and hinder energy production—in both isolated stem cells and mice possessing Dnmt3a mutations. In a related publication also released in Nature on the same day, Trowbridge and her collaborators reported that metformin—a common treatment for type 2 diabetes—also reduced the growth advantage of stem cells with the Dnmt3a mutation.
In their studies involving mice with both Dnmt3a mutations and clonal hematopoiesis, the drugs targeting mitochondria demonstrated significant efficacy. Within just a few days post-treatment, nearly 50% of the mutated cells perished, and the energy production among surviving mutant cells returned to standard levels. Normal cells, which do not depend as heavily on this metabolic pathway, remained unharmed.
“Observing this selective weakness, where the altered cells were compromised while healthy stem cells were unaffected, was incredibly encouraging,” stated Trowbridge.
Prospects for human treatment
The mitochondrial-targeting compounds were effective not only in murine models exhibiting clonal hematopoiesis but also in human blood stem cells that were genetically modified to include the DNMT3A mutation. These findings imply the potential for a similar approach to treating individuals with clonal hematopoiesis and could contribute to preventing blood cancers and various age-related disorders.
Nonetheless, further research is necessary to ascertain whether these therapeutic agents can effectively target other mutations linked to clonal hematopoiesis, as well as to evaluate their impact on cellular dynamics.
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