Telomere occupancy by TRF2 is altered by KIT mutations and correlates with mastocytosis regression
Year: 2025
Type: article
Abstract: 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.
Source: Blood Cancer Journal
Authors: 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
Institutions: Hôpital Necker-Enfants Malades, Inserm, Université Paris Cité, Institut Necker Enfants Malades, Assistance Publique – Hôpitaux de Paris, Institut des Maladies Génétiques Imagine, Sorbonne Université, Hôpital Tenon, Centre National de la Recherche Scientifique, Genopole (France), Université Paris-Saclay, Institut Gustave Roussy, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes, Aix-Marseille Université, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Université Paris Sciences et Lettres, Dynamique de l'information génétique : bases fondamentales et cancer, Institut Curie, Structure fédérative de recherche Necker, La Ligue Contre le Cancer, Pitié-Salpêtrière Hospital, Paris-Sorbonne University
Language: English
Topic: Mast cells and histamine
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,290
OpenAlex ID: W4415914068