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Open Full Page Published OnlineFirst July 25, 2019; DOI: 10.1158/2159-8290.CD-19-0138 RESEARCH ARTICLE Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis Florian Halbritter1,2, Matthias Farlik1,3, Raphaela Schwentner2, Gunhild Jug2, Nikolaus Fortelny1, Thomas Schnöller2, Hanja Pisa2, Linda C. Schuster1, Andrea Reinprecht4, Thomas Czech4, Johannes Gojo5, Wolfgang Holter2,5,6, Milen Minkov2,7, Wolfgang M. Bauer3, Ingrid Simonitsch-Klupp8, Christoph Bock1,9,10,11, and Caroline Hutter2,5,6 ABSTRACT Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory dis- eases, 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 puta- tive 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 tran- scriptomics 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. See related commentary by Gruber et al., p. 1343. 1CeMM Research Center for Molecular Medicine of the Austrian Acad- Note: Supplementary data for this article are available at Cancer Discovery emy of Sciences, Vienna, Austria. 2St. Anna Children’s Cancer Research Online (http://cancerdiscovery.aacrjournals.org/). 3 Institute (CCRI), Vienna, Austria. Department of Dermatology, Medical F. Halbritter and M. Farlik contributed equally to this work. University of Vienna, Vienna, Austria. 4Department of Neurosurgery, Medi- cal University of Vienna, Vienna, Austria. 5Department of Pediatrics, Medi- Corresponding Authors: Caroline Hutter, St. Anna Children’s Cancer cal University of Vienna, Vienna, Austria. 6St. Anna Children’s Hospital, Research Institute (CCRI), St. Anna Kinderkrebsforschung, Zimmer- St. Anna Kinderspital, Vienna, Austria. 7Department of Pediatrics, Adoles- mannplatz 10, 1090 Vienna, Austria. Phone: 4314-0470-4043; E-mail: cent Medicine and Neonatology, Rudolfstiftung Hospital, Vienna, Austria. [email protected]; and Christoph Bock, CeMM Research Center for 8Clinical Institute of Pathology, Medical University of Vienna, Vienna, Aus- Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, tria. 9Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria. E-mail: [email protected] Vienna, Austria. 10Max Planck Institute for Informatics, Saarland Informat- Cancer Discov 2019;9:1406–21 11 ics Campus, Saarbrücken, Germany. Ludwig Boltzmann Institute for Rare doi: 10.1158/2159-8290.CD-19-0138 and Undiagnosed Diseases, Vienna, Austria. ©2019 American Association for Cancer Research. 1406 | CANCER DISCOVERY OCTOBER 2019 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 25, 2019; DOI: 10.1158/2159-8290.CD-19-0138 INTRODUCTION BRAFV600E mutation (6–8), but the pathophysiology of LCH is different from cancers with oncogenic BRAFV600E mutations, Langerhans cell histiocytosis (LCH) is a rare hematopoietic such as melanoma, non–small cell lung cancer, and colorec- neoplasm driven by gain-of-function mutations in the MAPK tal cancer. LCH cells carry few genetic alterations beyond pathway (1, 2). The name of the disease originates from the BRAFV600E or another oncogenic driver in the MAPK pathway characteristic expression of CD207, also known as langerin, (MAP2K1, ARAF), and they show no progressive accumula- which is conventionally associated with Langerhans cells—a tion of recurrent somatic mutations (9). Instead, high levels type of resident epidermal immune cell (3). However, the rela- of inflammatory infiltrate suggest that cell-extrinsic, immu- tionship between LCH cells and Langerhans cells remains con- nologic stimuli could be key contributors to the formation of troversial, and LCH has also been linked to dendritic cells and LCH lesions (10–12). LCH is lethal in up to 20% of patients other myeloid cell types (4–6). LCH is phenotypically character- with risk organ–positive, multisystem disease treated accord- ized by an accumulation of CD1A and CD207 double-positive ing to current standard of care. In contrast, the disease often cells in various tissues (Fig. 1A). These lesions can develop in resolves spontaneously following unknown mechanisms in almost any organ, but are most common in skin and bone (1). patients with single lesions (1, 12). LCH severity is clinically assessed by the extent of the dis- ease (involvement of one or more organs, i.e., single-system RESULTS vs. multisystem disease) and the involvement of known risk organs (liver, spleen, hematopoietic system). Treatment deci- Langerhans Cell Histiocytosis Lesions Are sions are currently based solely on clinical presentation, as Composed of Distinct Cell Populations no reliable molecular markers for risk stratification have LCH cells within the same lesion show wide variability in been identified yet. LCH is most commonly driven by the their CD1A and CD207 levels based on IHC (Fig. 1B) and flow OCTOber 2019 CANCER DISCOVERY | 1407 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 25, 2019; DOI: 10.1158/2159-8290.CD-19-0138 RESEARCH ARTICLE Halbritter et al. A Langerhans cells histiocytosis (LCH) is a rare BELCH cells are Marker genes identify multiple cell types in single-cell transcriptome data of LCH lesions paediatric disease that affects various organs heterogeneous CD1A CD207 MAP2K1 CD33 BRAF Lesions formed by immune Bone lesion within biopsies Brain cells of unknown origin CD1A Cell surface markers: Lymph node CD1A, CD207 High Skin Genetic drivers: Lung Gain of MAPK signaling, CD3D IL32 FOXP3 CD19 CD79A V600E Liver 60% BRAF CD207 Spleen Incidence: Bone ∼4.6/million (age 0–15) Hematoxylin and eosin stain Skin lesion t-SNE dimension 2 IL3RACLEC4C TCF4 CD14 CD163 BRAFV600E Normalized UMI count Low t-SNE dimension 1 CDLCH biopsy samples analyzed using LCH biopsy samples analyzed using F Single-cell transcriptomics captures LCH cells single-cell transcriptome sequencing single-cell transcriptome sequencing and their microenvironment Identifier Biopsy Sex Age Extent Plasmacytoid CD1A+ CD207 + LCH_ELymph FemaleChild Multi- dendritic cells (LCH cells) node system LCH_H Skin Female Infant Multi- B cells system LCH_I Bone Male Child Single- system LCH_J Skin Female Aged Multi- system LCH_K Bone Male Child Single- system t-SNE dimension 2 LCH_N Skin Male Adult Multi- t-SNE dimension 2 system T cells LCH_O Bone Male Child Single- 19,044 single-cell Monocytes/ system transcriptomes macrophages t-SNE dimension 1 t-SNE dimension 1 Patient: EHIJKNO LCH cellImmune cell Figure 1. Single-cell transcriptome analysis captures cellular and molecular diversity of LCH lesions. A, Clinical presentation and incidence of LCH. Shown is an X-ray image of LCH bone lesions in the skull (top right), a photograph of extensive LCH skin lesions (bottom right), and a hematoxylin and eosin staining of an LCH biopsy (bottom left). B, Cellular heterogeneity in an LCH biopsy (lymph node), as revealed by immunostaining for CD1A, CD207, and an antibody that specifically detects mutated BRAFV600E protein. C, Overview of patient biopsy samples analyzed by single-cell RNA sequencing (RNA-seq) in this study. D, Low-dimensional projection (t-SNE plot) of the combined single-cell RNA-seq dataset across all analyzed biopsies, comprising a total of 19,044 single-cell transcriptome profiles. E, Molecular heterogeneity in LCH illustrated by low-dimensional projection (as in D) of all single-cell transcriptome profiles overlaid with the expression levels of selected marker genes (dark blue color indicates high expression levels). F, Cellular hetero- geneity in LCH illustrated by low-dimensional projection (as in D), annotated with cell types inferred from marker-gene expression. cytometry (Supplementary Fig. S1). To characterize the cel- Focusing initially on LCH-specific transcriptional profiles lular and molecular landscape of LCH lesions, we performed that were shared across cells and across patients, we com- droplet-based single-cell transcriptome sequencing of seven pared CD1A and CD207 marker–positive LCH cells with four LCH lesions. The biopsies were obtained from patients with immune-cell populations identified in all biopsies (Supple- multisystem disease (n = 4) and single-system disease (n = 3), mentary Fig. S2D). The LCH cells showed high expression of and they were collected
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