Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
01
02
2019
revised:
03
06
2019
accepted:
10
07
2019
pubmed:
28
7
2019
medline:
13
8
2020
entrez:
27
7
2019
Statut:
ppublish
Résumé
Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analyzed biopsies using IHC, and we defined an epigenomic and gene-regulatory basis of the different LCH-cell subsets by chromatin-accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions. SIGNIFICANCE: This study sketches a molecular portrait of LCH lesions by combining single-cell transcriptomics with epigenome profiling. We uncovered extensive cellular heterogeneity, explained in part by an intrinsic developmental hierarchy of LCH cells. Our findings provide new insights and hypotheses for advancing LCH research and a starting point for personalizing therapy.
Identifiants
pubmed: 31345789
pii: 2159-8290.CD-19-0138
doi: 10.1158/2159-8290.CD-19-0138
pmc: PMC6795548
mid: EMS84423
doi:
Substances chimiques
Biomarkers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1406-1421Subventions
Organisme : European Research Council
ID : 679146
Pays : International
Organisme : Austrian Science Fund FWF
ID : F 6102
Pays : Austria
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2019 American Association for Cancer Research.
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