KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

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^highF4/80⁺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^dimCD11b^intGr1^- 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.