Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells

• Published in: Blood 2012-12, Vol.120 (26), p.5199-5208
• Main Authors: Hutter, Caroline, Kauer, Max, Simonitsch-Klupp, Ingrid, Jug, Gunhild, Schwentner, Raphaela, Leitner, Judith, Bock, Peter, Steinberger, Peter, Bauer, Wolfgang, Carlesso, Nadia, Minkov, Milen, Gadner, Helmut, Stingl, Georg, Kovar, Heinrich, Kriehuber, Ernst
• Format: Article
• Language: English
• Subjects: Adolescent; Biological and medical sciences; Cell Differentiation - physiology; Cells, Cultured; Child; Child, Preschool; Dendritic Cells - metabolism; Dendritic Cells - pathology; Female; Hematologic and hematopoietic diseases; Histiocytosis, Langerhans-Cell - genetics; Histiocytosis, Langerhans-Cell - metabolism; Histiocytosis, Langerhans-Cell - pathology; Humans; Infant; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Jagged-2 Protein; Langerhans Cells - cytology; Langerhans Cells - metabolism; Langerhans Cells - pathology; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Other diseases. Hematologic involvement in other diseases; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Receptor, Notch1 - physiology; Transcriptome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-02-410241

Langerhans cell histiocytosis (LCH) is an enigmatic disease defined by the accumulation of Langerhans cell-like dendritic cells (DCs). In the present study, we demonstrate that LCH cells exhibit a unique transcription profile that separates them not only from plasmacytoid and myeloid DCs, but also from epidermal Langerhans cells, indicating a distinct DC entity. Molecular analysis revealed that isolated and tissue-bound LCH cells selectively express the Notch ligand Jagged 2 (JAG2) and are the only DCs that express both Notch ligand and its receptor. We further show that JAG2 signaling induces key LCH-cell markers in monocyte-derived DCs, suggesting a functional role of Notch signaling in LCH ontogenesis. JAG2 also induced matrix-metalloproteinases 1 and 12, which are highly expressed in LCH and may account for tissue destruction in LCH lesions. This induction was selective for DCs and was not recapitulated in monocytes. The results of the present study suggest that JAG2-mediated Notch activation confers phenotypic and functional aspects of LCH to DCs; therefore, interference with Notch signaling may be an attractive strategy to combat this disease.