Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology

• DOI: 10.1126/sciimmunol.add3330
• Publication Date: 2022-12-16T18:58:12Z
• Authors: Egle Kvedaraite; Paul Milne; Ahad Khalilnezhad; Marion Chevrier; Raman Sethi; Hong Kai Lee; Daniel W. Hagey; Tatiana von Bahr ...; Natalia Mouratidou; Martin Jädersten; Nicole Yee Shin Lee; Lara Minnerup; Yingrou Tan; Charles-Antoine D...; Nathan Benac; You Yi Hwang; Josephine Lum; Amos Hong Pheng Loh; Jessica Jansson; Karen Wei Weng Teng; Shabnam Khalilnezhad; Weili Xu; Anastasia Resteu; Hong Liang Tey; Ng Lai Guan; Anis Larbi; Shanshan Wu Howland; Henrik Arnell; Samir E. L. Andal...; Jorge Braier; Georgios Rassidakis; Laura Galluzzo; Andrzej Dzionek; Jan-Inge Henter; Jinmiao Chen; Matthew Collin; Florent Ginhoux
• Keywords: Langerhans Cell Histiocytosis; Monocyte; Cooperativity

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