| Literature DB >> 33958797 |
C Matthias Wilk1,2,3, Rikhia Chakraborty4, Steven T Chen1,2,3, Carl E Allen4, Miriam Merad5,6,7, Camille Bigenwald1,2,3, Jessica Le Berichel1,2,3, Alexandra Tabachnikova1,2,3, Rebecca Mancusi2,3, Harshal Abhyankar4, Maria Casanova-Acebes1,2,3, Ilaria Laface1,2,3, Guray Akturk1,2,3, Jenielle Jobson1,2,3, Zoi Karoulia1,2,3, Jerome C Martin1,2,3, John Grout1,2,3, Anahita Rafiei8, Howard Lin4, Markus G Manz8, Alessia Baccarini1,2,3, Poulikos I Poulikakos2,3, Brian D Brown1,2,3, Sacha Gnjatic1,2,3, Amaia Lujambio1,2,3, Kenneth L McClain4, Jennifer Picarsic9.
Abstract
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.Entities:
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Year: 2021 PMID： 33958797 PMCID： PMC9295868 DOI： 10.1038/s41591-021-01304-x
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 87.241