Abstract
Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm associated with somatic mutations in the genes involved in the RAF/MEK/extracellular signal-regulated kinase (ERK) signaling pathway. Recently, oncogenic mutations in NRAS/KRAS, upstream regulators of the RAF/MEK/ERK pathway, have been reported in pulmonary, but not in nonpulmonary, LCH cases, suggesting organ-specific contribution of oncogenic RAS to LCH pathogenesis. Using a mouse model expressing KRAS(G12D) in the lung by nasal delivery of adenoviral Cre recombinase (Cre), here we show that KRAS(G12D) expression in lung-resident myeloid cells induces pulmonary LCH-like neoplasms composed of pathogenic CD11c(high)F4/80(+)CD207(+) cells. The pathogenic cells were mitotically inactive, but proliferating precursors were detected in primary cultures of lung tissue. These precursors were derived, at least in part, from CD11c(dim)CD11b(int)Gr1(-) lung-resident monocytic cells transformed by KRAS(G12D) In contrast, BRAF(V600E) expression induced by the same method failed to develop LCH-like neoplasms, suggesting that each oncogene may initiate pulmonary LCH by transforming different types of lung-resident myeloid cells. In vivo treatment of the KRAS(G12D)-induced LCH-like mouse with the cholesterol-lowering drug atorvastatin ameliorated the pathology, implicating statins as potential therapeutics against a subset of pulmonary LCH.