TY - JOUR
T1 - BRAF V600E-induced senescence drives Langerhans cell histiocytosis pathophysiology
AU - Bigenwald, Camille
AU - Le Berichel, Jessica
AU - Wilk, C. Matthias
AU - Chakraborty, Rikhia
AU - Chen, Steven T.
AU - Tabachnikova, Alexandra
AU - Mancusi, Rebecca
AU - Abhyankar, Harshal
AU - Casanova-Acebes, Maria
AU - Laface, Ilaria
AU - Akturk, Guray
AU - Jobson, Jenielle
AU - Karoulia, Zoi
AU - Martin, Jerome C.
AU - Grout, John
AU - Rafiei, Anahita
AU - Lin, Howard
AU - Manz, Markus G.
AU - Baccarini, Alessia
AU - Poulikakos, Poulikos I.
AU - Brown, Brian D.
AU - Gnjatic, Sacha
AU - Lujambio, Amaia
AU - McClain, Kenneth L.
AU - Picarsic, Jennifer
AU - Allen, Carl E.
AU - Merad, Miriam
N1 - Funding Information:
We thank the Biorepository and Pathology Core and the Flow Cytometry Core Facilities at the Icahn School of Medicine at Mount Sinai for their technical expertise. We also thank K. Phaik Har Lim, T.-K. Man, T. Burke and B. Scull for their help with the generation of microarray sequencing data. We thank J. Kofler for kindly providing LCH-ND pictures and performing immunostaining. We thank L. Troncoso for her help. We thank C. Woods, image application specialist, Cincinnati Children’s Hospital Medical Center, for figure preparation for human studies (Fig. 4g) and J. Kofler, UPMC Division of Neuropathology, for creating Extended Data Fig. 4e. M.M. received funding from the National Institute of Health (R01 CA154947 and R01 CA190400). C.B. received fellowships from the Fondation pour la Recherche Médicale (FDM20170638478), from l’Institut Servier and from Assistance Publique Hôpitaux de Paris (Année Recherche). C.M.W. is supported by the Swiss National Science Foundation (SNSF PostDoc Mobility Fellowship P400PM_186740) and by the Swiss Cancer League (grant for bursaries BIL KFS 4724-02-2019). We thank the research coordinators of the Histio–Lymphoma team at Texas Children’s Cancer Center for their help with patient sample collection. The TXCH Histiocytosis Program is supported by a research grant from the HistioCure Foundation. This work was supported by the Department of Defense through the Peer Reviewed Cancer Research Program under award no. W81XWH-19-1-0167 (R.C.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105414377&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01304-x
DO - 10.1038/s41591-021-01304-x
M3 - Article
C2 - 33958797
AN - SCOPUS:85105414377
VL - 27
SP - 851
EP - 861
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 5
ER -