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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish
Pages (from-to)851-861
Number of pages11
JournalNature Medicine
Volume27
Issue number5
DOIs
StatePublished - May 2021

Fingerprint

Dive into the research topics of 'BRAF V600E-induced senescence drives Langerhans cell histiocytosis pathophysiology'. Together they form a unique fingerprint.

Cite this