JAG2 signaling induces differentiation of CD14+ monocytes into Langerhans cell histiocytosis-like cells

Abstract

Langerhans cell histiocytosis (LCH) is a MAPK pathway-driven disease characterized by the accumulation of CD1a + langerin + cells of unknown origin. We have previously reported that the Notch signaling pathway is active in LCH lesions and that the Notch ligand Jagged2 (JAG2) induces CD1a and langerin expression in monocytes in vitro. Here we show that Notch signaling induces monocytes to acquire an LCH gene signature and that Notch inhibition suppresses the LCH phenotype.In contrast, while also CD1c + dendritic cells or IL-4-stimulated CD14 + monocytes acquire CD1a and langerin positivity in culture, their gene expression profiles and surface phenotypes are more different from primary LCH cells. We propose a model where CD14 + monocytes serve as LCH cell precursor and JAG2-mediated activation of the Notch signaling pathway initiates a differentiation of monocytes toward LCH cells in selected niches and thereby contributes to LCH pathogenesis. K E Y W O R D SBRAFV600E, notch pathway, pediatric neoplasm BRAFV600E mutation alone is not instructive for a cell to develop an LCH phenotype.We have previously shown that the Notch pathway is active in LCH and that stimulation of the Notch pathway in the presence of

CSF1R Is Required for Differentiation and Migration of Langerhans Cells and Langerhans Cell Histiocytosis

“…High serum concentrations of TGF and CSF-1 have been found in LCH patients, suggesting their contribution in the differentiation of tissue-infiltrating neoplastic LCs from hematopoietic precursors (48). Transcriptomic studies revealed a monocyte-LC signature for LCH cells driven by JAG2-mediated activation of Notch (49). We observed a hybrid phenotype of BRAF V600E LCH cells, with cDC2 markers (BDCA1 + and IRF4 + ) admixed to LC markers (CD1a, CD207, and CSF1R) indicating that a partial LC commitment of cDC2 circulating precursors might also occur.…”

Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis

“…The mutation was present in all cellular subsets tested, although at much higher frequency in myeloid lineage cells (Figure 2B). While BRAF V600E has also been described in CD19 + B lymphocytes 24 and CD3 + lymphocytes 25 , this is the first description of BRAF V600E in NK cells and granulocytes.…”

Circulating CD1c+ myeloid dendritic cells are potential precursors to LCH lesion CD1a+CD207+ cells

“…14,15,17,31 Furthermore, a recent study showed that CD14 1 monocytes could acquire gene signature with similarities to the LCH CD1a 1 CD207 1 cell signature in the presence of Notch ligands JAG2 in vitro. 45 It remains possible that CD14 1 monocytes could differentiate rapidly into LCH CD1a 1 CD207 1 DCs once entering the lesion, or that a small population of CD14 1 DCs that present in LCH lesions may not be captured by the experiments in this study. Notably, unlike a previous report, 46 we did not detect any CD207 1 cells in peripheral blood of either LCH patients (high or low risk) or healthy controls (supplemental Figure 9).…”

“…Given the ability to differentiate into langerin 1 (CD207 1 ) cells in vitro, both CD1c 1 mDCs and CD14 1 monocytes are potential candidates to give rise to LCH CD1a 1 CD207 1 DCs. 14,15,17,31,45 To determine the differentiation pathway(s) of LCH CD1a 1 CD207 1 DCs, we first compared the gene-expression profiles of CD1a 1 CD207 1 DCs to gene signatures from human myeloid cell lineages. LCH CD1a 1 CD207 1 cells were most highly enriched with CD1c 1 mDC signature, with relatively lower enrichment with the CD14 1 monocyte signature using both CMAP and BubbleGum analysis platforms (Figure 2A-B).…”