Genetic changes in four specific genes may help explain why systemic mastocytosis (SM) develops, according to research published recently in Clinical and Translational Allergy.
These results confirm earlier work suggesting that changes in TET2, DNMT3A, SETD2 and BRD4 play a role in SM, and two of the changes have never been seen before. For patients, this information could lead to a clearer picture of what drives the disease and possibly new directions for treatment in the future.
This study included 32 people with indolent SM, half women and half men, and 16 healthy volunteers matched by age and sex. Blood samples from all participants were studied with next-generation sequencing, a method that reads DNA in great detail. Out of more than 4,200 variations studied, five stood out as significantly different between patients and healthy individuals. Two were in the TET2 gene on chromosome 4, and one each in DNMT3A, SETD2 and BRD4, located on chromosomes 2, 3 and 19.
“[T]he functional enrichment implicated pathways occur in transcriptional regulation, multicellular development and signal transduction,” stated the authors of this study. They continued, “These results support the routine implementation of advanced technologies, such as droplet digital PCR and NGS [next-generation sequencing] to diagnostic and therapeutic strategies for mastocytosis.”
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All four genes are known to help regulate how DNA is read and how cells behave. In mastocytosis, mast cells grow and react in ways that cause problems, such as severe allergic responses. Alterations in these genes may disturb the normal balance, leading to overactive or abnormal mast cells. One mutation in DNMT3A was especially notable: a small deletion that disrupts the gene’s ability to produce a working protein, which may allow mast cells to multiply or respond in harmful ways.
Researchers carried out several checks to ensure the accuracy of their results. The sequencing run produced over 3 million DNA reads, and 84% were properly mapped to their targets. Even though the run started with a higher-than-ideal density, quality controls and computer tools confirmed the results were trustworthy.
These discoveries suggest that epigenetic regulator genes, which are those that manage how DNA functions without changing its sequence, may be key in the origins of SM. This adds to the well-known role of the KIT mutation but shows that other pathways are also important.
For patients, the immediate impact is not new treatment but a better understanding of the disease. Knowing which genes are involved may eventually help researchers create more focused therapies and guide doctors in predicting how SM will progress.
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