Lineage-switching of the cellular distribution of BRAFV600E in multisystem Langerhans cell histiocytosis.

The majority of children with high-risk LCH have BRAFV600E mutation. BRAFV600E alleles are detectable in myeloid mononuclear cells at diagnosis but it is not known if the cellular distribution of mutation evolves over time. Here, the profiles of 16 high risk patients were analyzed. Two received conventional salvage chemotherapy, 4 patients on inhibitors were tracked at intervals for 3-6 years and 10 patients, also given inhibitors, were analyzed once more than 2 years after diagnosis. In contrast to patients responding to salvage chemotherapy, who completely cleared BRAFV600E within six months, children who received inhibitors maintained high BRAFV600E alleles in their blood. At diagnosis, mutation was detected predominantly in monocytes and myeloid dendritic cells. With time, mutation switched to the T cell compartment, which accounted for most of the mutational burden in PBMC more than two years from diagnosis (median 85.4%; range 44.5-100%). The highest level of mutation occurred in naïve CD4+ T cells (median 51.2%; range 3.8-93.5%). This study reveals an unexpected lineage-switch of BRAFV600E mutation in high risk LCH, which may influence monitoring strategies for the potential withdrawal of inhibitor treatment and has new implications for the pathogenesis of neurodegeneration, which occurred in 4 patients.