Langerhans Cell Histiocytosis (LCH) is a human myeloid cell neoplasia that has recently been associated with the presence of BRAFV600E mutations in lesions. Although it was previously unclear whether these BRAF mutations were simply passenger mutations or drivers of pathogenesis, our lab recently established a mouse model of LCH, demonstrating that BRAFV600E expression under the CD11c promoter in dendritic cells (CD11c-BRAFV600E) is sufficient to recapitulate a syndrome resembling high-risk human LCH. Our preliminary analysis of CD11c-BRAFV600E dendritic cells reveals pathogenic accumulation of immature dendritic cells displaying reduced expression of dendritic cell maturation/migration markers (MHCII, CD40, CCR7) accompanied by increased phospho-ERK (pERK) in dendritic cells (DC). The mechanisms linking ERK to suppression of DC maturation and LCH pathogenesis are not clear, but we hypothesize that targeted rescue of DC maturation may present novel therapeutic options for treating clinical LCH. Thus, in Aims 1 and 2 this proposal, our goal is to delineate the mechanism by which the RAF/MEK/ERK pathway suppresses dendritic cell maturation in a mouse model of LCH.
In Aim 3, we will test the in vivo efficacy of novel drug targets that we identify from Aim 2. In this manner, our goal is to reveal novel mechanisms regulating DC maturation and validate potential drug targets to guide development of novel LCH therapies.
This proposal seeks to reveal the molecular mechanisms by which the RAF/MEK/ERK pathway suppresses dendritic cell (DC) maturation in Langerhans Cell Histiocytosis (LCH). We hypothesize that rescue of DC maturation may alleviate the pathogenic accumulation of immature DC during LCH. These proposed studies may reveal novel aspects of DC biology and may reveal novel therapeutic avenues for treating LCH patients.
| Hogstad, Brandon; Berres, Marie-Luise; Chakraborty, Rikhia et al. (2018) RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. J Exp Med 215:319-336 |
