Children with mastocytosis may experience spontaneous remission because their mast cells age and stop dividing, according to results from a study published recently in Blood Cancer Journal.
Researchers found that this process, known as cellular senescence, is linked to shortened telomeres in mast cells carrying certain genetic mutations. Telomeres are protective caps on the ends of chromosomes that shorten with cell divisions and signal cells to stop growing when they become too short.
“Our study uncovers a previously unrecognized role of telomere biology in mastocytosis, demonstrating that KIT mutation subtypes dictate mast cell fate through differential effects on telomere stability and senescence,” explained the study’s authors.
Mastocytosis occurs in both children and adults, but its behavior differs by age. Adults typically have systemic mastocytosis (SM), a chronic, lifelong disease driven by mutations in a gene called KIT, most often in a region known as the phospho-transferase domain (PTD). In contrast, children frequently have cutaneous mastocytosis, a form of mastocytosis that mainly impacts the skin, and non-PTD KIT mutations that affect different regions of the gene. In children, the disease often fades naturally over time, though in some cases it can progress into SM.
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In a French study involving 1,267 patients, nearly all adults (98.4%) had PTD KIT mutations, whereas about half of children had non-PTD mutations. Only three of the 52 adults with childhood-onset disease carried a non-PTD mutation, suggesting these mutations are linked to remission.
To explore why, investigators compared two versions of KIT: the adult-type mutation KIT D816V and a pediatric-type mutation KIT Del417/8+D419Y. Cells with the pediatric mutation developed shorter telomeres and showed stronger signs of senescence, while those with the adult mutation maintained longer telomeres and kept dividing. This pattern was confirmed in lab studies and in skin samples from young patients.
The team discovered that in children’s mast cells, the pediatric-type mutation activated a signaling protein called p38 MAP-kinase, which alters another protein, TRF2, that normally protects telomeres. When TRF2 is displaced, telomeres shorten more quickly, prompting the cells to stop dividing. Blocking p38 MAP-kinase prevented telomere shortening and reversed the effect in experimental models.
For patients and families, these results may explain why mastocytosis often improves or disappears during childhood but persists in adults. Understanding how telomere biology and gene signaling differ between age groups could eventually help scientists design treatments that mimic this natural “self-healing” process, offering new hope for patients with SM.
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