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Dissecting the Transcriptomic Landscape of Circulating Mononuclear Phagocytes in Langerhans Cell Histiocytosis at Single-cell Level

ABSTRACT: Langerhans cell histiocytosis (LCH) is a rarely clonal disorder caused by aberrant activation of MAPK pathway, which predominantly affects the mononuclear myeloid lineages. Many efforts have been devoted to tracking precursor cells in circulating blood and bone marrow by detection of BRAFV600E alleles and to exploring the differentiation potential of LCH-related myeloid cells in vitro. However, their cellular and molecular alterations remain unclear. Here, we constructed a single-cell transcriptional landscape of more than 3,000 monocytes and DCs from treatment-naïve pediatric LCH and targeted-therapy pediatric LCH cohorts, unraveling patient to patient heterogeneity and underlying molecular mechanisms of BRAF inhibitor, respectively. In parallel, we further investigated the precise relationship between circulating potential precursors and pathological LCH clusters based on unbiased joint analysis. In addition, we found that the proportion of pDC in Lin-HLA-DR+ population is closely linked with the severity of the disease, providing a novel promising indicator to optimize the stratification strategy. Taken together, our data update the molecular understanding of LCH biology, which might contribute to improvement of clinical therapeutics and promotion of the personalized medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151713 | GEO | 2021/09/15

REPOSITORIES: GEO

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Project description:Langerhans-cell histiocytosis (LCH) is characterized by heterogeneous lesions containing CD207+ Langerhans cells (LCs) and lymphocytes. In this study, we isolated CD207+ cells and CD3+ T cells from LCH lesions to determine cell-specific gene expression. Compared to control epidermal CD207+ cells, the LCH CD207+ cells yielded 2113 differentially-expressed genes (FDR<0.01). Surprisingly, expression of many genes previously associated with LCH, including cell-cycle regulators, pro-inflammatory cytokines and chemokines were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly over-expressed in LCH CD207+ cells. Furthermore, several genes associated with immature myeloid dendritic cells were over-expressed in LCH CD207+ cells. Compared to the peripheral CD3+ cells from LCH patients, the LCH lesion CD3+ cells yielded only 162 differentially-regulated genes (FDR<0.01), and the expression profile of the LCH lesion CD3+ cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4 as well as SPP1. Based on these results, we propose a new model of LCH pathogenesis in which lesions do not arise from epidermal Langerhans cells, but from accumulation of bone-marrow derived immature myeloid dendritic cells that recruit activated lymphocytes. Cell-specific gene expression from LCH biopsy specimens was evaluated by comparing hybridization signal from amplified cDNA on Affymetrix gene chips (U133A Plus 2.0) (Table1). Three sets of comparisons were performed: 1) Thirteen LCH CD207+ samples were compared to 12 control skin LCH CD207+ samples. 2) Seven LCH lesion CD3+ samples were compared to 7 peripheral blood CD3+ samples from the same patients. 3) Twelve LCH lesion CD3+ samples were compared to 4 pooled control tonsil CD3+ samples (5 individual tonsil CD3+ samples/pool).

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Dissecting the Transcriptomic Landscape of Circulating Mononuclear Phagocytes in Langerhans Cell Histiocytosis at Single-cell Level

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