It's a rare and precious genetic variant for those fortunate enough to carry it. Known scientifically as rs17834140-T, it was recently discovered by an American team. It can reduce an individual's risk of leukemia and slow the progression of the disease in those affected. This provides important insight into why some people are naturally more resistant to developing blood cancers.
With age, and as tissues age, they silently accumulate numerous mutations that can promote cancer. These mutations also affect hematopoiesis, the set of mechanisms involved in the production of various blood cells. And this occurs even in healthy individuals.
In everyone, blood stem cells, called hematopoietic stem cells, produce and renew all blood cells throughout life. A stem cell can divide and give rise to new cells. All the resulting cells then carry the same mutations as the original cell. These are called "clones." However, sometimes, clones of mutated blood stem cells become more numerous than others, without any cancer or symptoms yet appearing. This condition, called CHIP (clonal hematopoiesis of undetermined potential), is not a disease in itself but rather a risk factor. Some clones of mutated stem cells even remain stable or decrease over time, suggesting that hereditary and/or environmental factors can inhibit or slow down the process.
“ Most research has focused on the reasons why the risk of cancer increases. For example, individuals with immune problems or impaired DNA repair.", explains to Science and Future the first author of this work, Dr. Gaurav Agarwal, of the Broad Institute and Harvard Medical School (United States). “ In this study, we turn the question around and ask — for the first time — why some people do not develop cancer. »
To try to understand why some people in the population seem to resist these mutations, the team conducted a meta-analysis including more than 640,000 individuals, searching for inherited DNA variants with a protective effect. This is how they identified rs17834140-T, a genetic variant that reduces the likelihood of developing blood cancers. On its own, it is capable of triggering a whole cascade of genetic effects.
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Stopping an entire genetic cascade
It was already known that the MSI2 gene is crucial for the maintenance and proliferation of blood stem cells. When its activity decreases, the cells become less capable of excessive multiplication. For MSI2 to function normally, a transcription factor called GATA-2 binds to DNA to activate the expression of the MSI2 gene. However, the newly discovered gene, rs17834140-T, disrupts the binding site. GATA-2 binds less effectively, and the MSI2 gene is expressed less, resulting in a broad protective effect. MSI2 does not control a single gene, but rather an entire network of genes that helps mutated stem cells maintain and multiply. When MSI2 is weakened, the entire network of genes that it supports is also weakened.
These results offer researchers hope for new treatment avenues. Our results show that some people are naturally protected against blood cancers because their blood stem cells function with lower MSI2 activity. This provides human genetic evidence that replicating this state—by targeting MSI2 or its downstream RNA network—could be used to prevent leukemia in high-risk individuals, or to treat patients with the disease already established." explains Dr. Agarwal.
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Between 1 and 5% of the population carries this valuable gene
This is especially significant given that MSI2 and its network appear to play a central role in the severity of blood cancers. The study shows that this same gene network is highly active in stem cells carrying high-risk cancer mutations, as well as in children with acute myeloid leukemiaIn these cases, high network activity is associated with a more aggressive disease and lower survival.
The study has just been published in the journal ScienceThe team is already at the next stage. They are currently conducting additional preclinical studies to determine the most effective strategies for targeting MSI2 and to identify the patient populations most likely to benefit from them. More broadly, we use inherited genetic variations as a lens to highlight other biological pathways that confer resilience to cancer. Our goal is to develop new therapeutic approaches that not only treat leukemia but could ultimately help prevent it. "Currently, between 1 and 5% of the population would carry this precious gene, inherited from their parents.
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