Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis

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...

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Bibliographic Details
Published in:Cancer discovery 2019-10, Vol.9 (10), p.1406-1421
Main Authors: Halbritter, Florian, Farlik, Matthias, Schwentner, Raphaela, Jug, Gunhild, Fortelny, Nikolaus, Schnöller, Thomas, Pisa, Hanja, Schuster, Linda C, Reinprecht, Andrea, Czech, Thomas, Gojo, Johannes, Holter, Wolfgang, Minkov, Milen, Bauer, Wolfgang M, Simonitsch-Klupp, Ingrid, Bock, Christoph, Hutter, Caroline
Format: Article
Language:English
Subjects:
Biomarkers
Biopsy
Disease Susceptibility
Epigenesis, Genetic
Epigenomics - methods
Gene Expression Profiling
Gene Expression Regulation
High-Throughput Nucleotide Sequencing
Histiocytosis, Langerhans-Cell - diagnosis
Histiocytosis, Langerhans-Cell - genetics
Histiocytosis, Langerhans-Cell - metabolism
Humans
Immunohistochemistry
Radiography
Single-Cell Analysis
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Summary: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. . .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-19-0138