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<p>Mastocytosis, a clonal disorder characterized by the accumulation of mast cells in various tissues, affects both adults and children. Adults frequently exhibit <i>KIT</i> activating mutations, usually in the phospho-transferase domain (PTD <i>KIT</i> mutations). Our previous findings revealed that children also harbor oncogenic <i>KIT</i> activating mutations, but more commonly within the extra-cellular domain (non-PTD <i>KIT</i> mutations). While the disease persists chronically in adults, it often regresses spontaneously in children through an unknown mechanism. Here, we report that tumor senescence in childhood mastocytosis may be triggered by significantly shortened telomeres in mast cells harboring non-PTD <i>KIT</i> mutations compared to those with PTD <i>KIT</i> mutations. In vitro models further demonstrated a senescent phenotype associated with shorter telomeres for the non-PTD <i>KIT</i> mutant compared to the PTD <i>KIT</i> mutant. Mechanistically, we found that telomere shortening in mast cells from children with non-PTD <i>KIT</i> mutations is linked with increased p38 MAP-kinase activation, resulting in lower TRF2 occupancy on telomeres. Thus, non-PTD <i>KIT</i> mutations trigger distinct signaling pathways leading to telomere shortening and cellular senescence, providing mechanistic insights into the differing outcomes between childhood- and adult-onset mastocytosis.</p>

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Telomere occupancy by TRF2 is altered by KIT mutations and correlates with mastocytosis regression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月5日

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  • Julie Bruneau,
  • Sophie Georgin-Lavialle,
  • Sophia Ladraa,
  • Zakia Belaid,
  • Isabelle Plo,
  • Sébastien Letard,
  • Erinn Soucie,
  • Irena Draskovic,
  • Nicolas Goudin,
  • Marie Bouillié,
  • Yves Lepelletier,
  • Julien Rossignol,
  • Laura Polivka,
  • Laurent Frenzel,
  • Olivier Lortholary,
  • Sylvie Fraitag,
  • Christine Bodemer,
  • Patrick Revy,
  • Michel Arock,
  • Thierry-Jo Molina,
  • Arturo Londono-Vallejo,
  • Patrice Dubreuil,
  • Leila Maouche-Chretien,
  • Olivier Hermine

摘要

Mastocytosis, a clonal disorder characterized by the accumulation of mast cells in various tissues, affects both adults and children. Adults frequently exhibit KIT activating mutations, usually in the phospho-transferase domain (PTD KIT mutations). Our previous findings revealed that children also harbor oncogenic KIT activating mutations, but more commonly within the extra-cellular domain (non-PTD KIT mutations). While the disease persists chronically in adults, it often regresses spontaneously in children through an unknown mechanism. Here, we report that tumor senescence in childhood mastocytosis may be triggered by significantly shortened telomeres in mast cells harboring non-PTD KIT mutations compared to those with PTD KIT mutations. In vitro models further demonstrated a senescent phenotype associated with shorter telomeres for the non-PTD KIT mutant compared to the PTD KIT mutant. Mechanistically, we found that telomere shortening in mast cells from children with non-PTD KIT mutations is linked with increased p38 MAP-kinase activation, resulting in lower TRF2 occupancy on telomeres. Thus, non-PTD KIT mutations trigger distinct signaling pathways leading to telomere shortening and cellular senescence, providing mechanistic insights into the differing outcomes between childhood- and adult-onset mastocytosis.