Novel Animal Model for LCH
Icahn School of Medicine at Mount Sinai, New York, New York USA
Date of Award
Amount of Award
Langerhans cell histiocytosis (LCH) is a disease characterized by the abnormal proliferation of leukocytes in the liver, lung and spleen. Approximately 60% of the patients with LCH carry a mutation in a gene (BRAF) that controls cell growth. Results from our lab indicate that expression of this mutated BRAF gene (BRAFV600E) induces a disease in mice that has several similarities with human LCH. In this proposal we will define which cell is important for development of disease in the mouse model and how it causes disease. These experiments should provide important new clues on the origin of LCH and define novel pathways for its prevention and cure.
Twelve Month Report
Langerhans cell histiocytosis (LCH) is a disease characterized by the abnormal proliferation of cells of the mononuclear phagocytic system (dendritic cells and monocytes) in the liver, lung and spleen. It was recently shown that a mutated form of Braf, an oncogene that is involved in directing cell growth, is present in 60% of the patients with LCH. Data from our lab showed that expression of the mutated form of Braf in cells of the monocytes induced LCH-like disease in mice (these animals are called FRBRAF mice). This experimental disease shared several similarities with human LCH. In this proposal we investigated the phenotype, gene expression profile and origin of the cell type that cause LCH in the FRBRAF mice. We found that transplant of bone marrow cells from a BRAF mouse into a normal recipient animal promoted development of a LCH-like disease in the liver, spleen and lung but not in the brain. We also performed gene expression analysis of FRBRAF livers and of isolated monocytes that expressed the BRAFV600E mutation. We found that several genes that were altered in human LCH were also altered in FRBRAF mice. We concluded that monocytes expressing the mutated form of Braf are the cell of origin of systemic LCH in mice.