Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm, characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase pathway activation. LCH cells may trigger destructive pathology yet remain in precarious state, finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well-known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity, and comparing LCH cells with normal MNPs within lesions. We found LCH-discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/Monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch dependent cooperativity between DC2 and DC3/monocyte lineages, during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring prior to fate commitment to DC2 and DC3/Monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
https://creativecommons.org/licenses/by/4.0/This work is licensed under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license.