BRAF V600E-induced senescence drives Langerhans cell histiocytosis pathophysiology

Camille Bigenwald, Jessica Le Berichel, C. Matthias Wilk, Rikhia Chakraborty, Steven T. Chen, Alexandra Tabachnikova, Rebecca Mancusi, Harshal Abhyankar, Maria Casanova-Acebes, Ilaria Laface, Guray Akturk, Jenielle Jobson, Zoi Karoulia, Jerome C. Martin, John Grout, Anahita Rafiei, Howard Lin, Markus G. Manz, Alessia Baccarini, Poulikos I. PoulikakosBrian D. Brown, Sacha Gnjatic, Amaia Lujambio, Kenneth L. McClain, Jennifer Picarsic, Carl E. Allen, Miriam Merad

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

43 Citations (Scopus)

Résumé

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 BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAFV600E mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAFV600E 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.

langue originaleAnglais
Pages (de - à)851-861
Nombre de pages11
journalNature Medicine
Volume27
Numéro de publication5
Les DOIs
étatPublié - 1 mai 2021
Modification externeOui

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