期刊
NATURE MEDICINE
卷 27, 期 5, 页码 851-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01304-x
关键词
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资金
- National Institute of Health [R01 CA154947, R01 CA190400]
- Fondation pour la Recherche Medicale [FDM20170638478]
- Swiss National Science Foundation (SNSF PostDoc Mobility Fellowship) [P400PM_186740]
- Swiss Cancer League [BIL KFS 4724-02-2019]
- HistioCure Foundation
- Department of Defense through the Peer Reviewed Cancer Research Program [W81XWH-19-1-0167]
- l'Institut Servier and from Assistance Publique Hopitaux de Paris (Annee Recherche)
- Swiss National Science Foundation (SNF) [P400PM_186740] Funding Source: Swiss National Science Foundation (SNF)
The study found that the BRAF(V600E) mutation induces a senescence program in multipotent hematopoietic progenitor cells, leading to the development of LCH disease, suggesting that senescent cells may be a new target for the treatment of LCH.
Senescence of hematopoietic progenitor cells, enforced by the BRAF(V600E) mutation, underlies the development of Langerhans cell histiocytosis and could be a new target for drug development and therapy of this disease in patients. Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAF(V600E). We recently discovered that the BRAF(V600E) mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAF(V600E) mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAF(V600E) mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.
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