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

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.

Authors

Institutions

Publication Details

Journal
Blood Cancer Journal
Published
2025-11-05
DOI
https://doi.org/10.1038/s41408-025-01372-z
Primary Topic
Mast cells and histamine
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Isabelle Plo, Sylvie Fraitag, Julien Rossignol, Marie Bouillié et al.
Blood Cancer Journal
Mast cells and histamine
article

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

Isabelle Plo, Sylvie Fraitag, Julien Rossignol, Marie Bouillié, Irena Drašković, Stany Chrétien, Arturo Londoño‐Vallejo, Sébastien Letard, Laura Polivka, Zakia Belaid, Patrick Revy, Julie Bruneau, Erinn Soucié, Sophia Ladraa, Yves Lepelletier, Michel Arock, Nicolas Goudin, Patrice Dubreuil, Sophie Georgin-Lavialle, Christine Bodemer, Olivier Hermine, Thierry Jo Molina, Laurent Frenzel, Olivier Lortholary
article en

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.

Blood Cancer JournalVol. 15(1)
Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris Cité (FR), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Sorbonne Université (FR), Institut Necker Enfants Malades (FR), La Ligue Contre le Cancer (FR), Assistance Publique – Hôpitaux de Paris (FR), Dynamique de l'information génétique : bases fondamentales et cancer (FR), Laboratoire National de Référence (MA), Pitié-Salpêtrière Hospital (FR), Genopole (France) (FR), Centre de Recherche en Cancérologie de Marseille (FR), Hôpital des Enfants (FR), Hôpital Tenon (FR)
Openalex Percentile: Top 65%
Mast cells and histamine
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.