Oncogenic signalling and host immunocompetency govern senescent cell clearance and systemic inflammation in a mouse model of oncogene-induced senescence
Abstract
Senescence is a stress-induced program defined by permanent cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP). Defective clearance of senescent cells promotes inflammation, tissue dysfunction, and ageing, yet determinants of their elimination remain poorly understood. Here, we model oncogene-induced senescence in the hematopoietic system by transplanting Braf V600E - or Braf ΔN -expressing hematopoietic stem and progenitor cells into recipients with distinct immune backgrounds. Braf V600E induces a stronger senescence program and more aggressive disease than Braf ΔN . Survival depends on oncogene-expressing cell burden and host immunity: immunocompetent, lower-burden mice clear oncogene-expressing cells and survive long-term, whereas higher-burden mice show checkpoint upregulation, T-cell exhaustion, and early death. NSG, Rag1KO, and lymphocyte-depleted hosts fail to clear these cells, developing sustained inflammation and bone marrow failure. Rapamycin administration attenuates senescence-associated features and improves survival. These findings identify oncogenic intensity and adaptive immune competence as coupled determinants of senescent-cell fate, with implications for chronic inflammation and senescence-targeted therapies.
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BibTeX
@article{colleoni2026oncogenic,
title = {{Oncogenic signalling and host immunocompetency govern senescent cell clearance and systemic inflammation in a mouse model of oncogene-induced senescence}},
author = {Cristina Colleoni and Leonardo Ormoli and Pierangela Gallina and Laura Rudilosso and Fabrizio Benedicenti and Martina Rocchi and Rossana Norata and Sara Degl’Innocenti and Tommaso Sconocchia and Kety Giannetti and Dimitri Bulté and Anna Villa and Alessandra Mortellaro and Raffaella Di Micco and Ivan Merelli and Francesca Sanvito and Daniela Cesana and Eugenio Montini},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-79038-y},
url = {https://www.nature.com/articles/s41467-026-79038-y},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Oncogenic signalling and host immunocompetency govern senescent cell clearance and systemic inflammation in a mouse model of oncogene-induced senescence
AU - Cristina Colleoni
AU - Leonardo Ormoli
AU - Pierangela Gallina
AU - Laura Rudilosso
AU - Fabrizio Benedicenti
AU - Martina Rocchi
AU - Rossana Norata
AU - Sara Degl’Innocenti
AU - Tommaso Sconocchia
AU - Kety Giannetti
AU - Dimitri Bulté
AU - Anna Villa
AU - Alessandra Mortellaro
AU - Raffaella Di Micco
AU - Ivan Merelli
AU - Francesca Sanvito
AU - Daniela Cesana
AU - Eugenio Montini
PY - 2026
DA - 2026/10/20
JO - Nature Communications
DO - 10.1038/s41467-026-79038-y
UR - https://www.nature.com/articles/s41467-026-79038-y
AB - Senescence is a stress-induced program defined by permanent cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP). Defective clearance of senescent cells promotes inflammation, tissue dysfunction, and ageing, yet determinants of their elimination remain poorly understood. Here, we model oncogene-induced senescence in the hematopoietic system by transplanting Braf V600E - or Braf ΔN -expressing hematopoietic stem and progenitor cells into recipients with distinct immune backgrounds. Braf V600E induces a stronger senescence program and more aggressive disease than Braf ΔN . Survival depends on oncogene-expressing cell burden and host immunity: immunocompetent, lower-burden mice clear oncogene-expressing cells and survive long-term, whereas higher-burden mice show checkpoint upregulation, T-cell exhaustion, and early death. NSG, Rag1KO, and lymphocyte-depleted hosts fail to clear these cells, developing sustained inflammation and bone marrow failure. Rapamycin administration attenuates senescence-associated features and improves survival. These findings identify oncogenic intensity and adaptive immune competence as coupled determinants of senescent-cell fate, with implications for chronic inflammation and senescence-targeted therapies.
SN - 2041-1723
ER -