Transcriptomic landscape of circulating mononuclear phagocytes in Langerhans cell histiocytosis at the single-cell level

Hui Shi, Han He, Lei Cui, Egle Kvedaraite, Zhilei Bian, Tao Huang, Christopher Z.W. Lee, Zhigang Li, Jian He, Yandong Gong, Zongcheng Li, Jie Zhou, Yang Zeng, Xianlong Li, Yanli Ni, Zhijie Bai, Chen Liu, Na Li, Honghao Ma, Dong WangYu Lan, Florent Ginhoux, Rui Zhang, Bing Liu

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

16 Citations (Scopus)

Résumé

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm caused by aberrant activation of the mitogen-activated protein kinase (MAPK) pathway. Circulating myeloid cells from patients often carry disease-associated mutations and can be differentiated into langerinhigh LCH-like cells in vitro, but their detailed immune-phenotypic and molecular profiles are lacking and could shed key insights into disease biology. Here we recruited 217 pediatric LCH patients and took blood and tissue samples for BRAFV600E analysis. Immune-phenotyping of the circulating LinHLA-DR+ immune population in 49 of these patients revealed that decreased frequency of plasmacytoid dendritic cells was significantly linked to disease severity. By single-cell RNA sequencing of samples from 14 patients, we identified key changes in expression of RAS-MAPK-extracellular signal-regulated kinase (ERK) signaling-related genes and transcription factors in distinct members of the mononuclear phagocyte system in the presence of BRAFV600E. Moreover, treatment of patients with the BRAF inhibitor dabrafenib resulted in MAPK cascade inhibition, inflammation prevention, and regulation of cellular metabolism within mononuclear phagocytes. Finally, we also observed elevated expression of RAS-MAPK-ERK signaling-related genes in a CD207+CD1a+ cell subcluster in skin. Taken together, our data extend the molecular understanding of LCH biology at single-cell resolution, which might contribute to improvement of clinical diagnostics and therapeutics, and aid in the development of personalized medicine approaches.

langue originaleAnglais
Pages (de - à)1237-1248
Nombre de pages12
journalBlood
Volume138
Numéro de publication14
Les DOIs
étatPublié - 7 oct. 2021
Modification externeOui

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