Lineage switching of the cellular distribution of BRAF(V600E) in multisystem Langerhans cell histiocytosis

Most children with high-risk Langerhans cell histiocytosis (LCH) have BRAF(V600E) mutation. BRAF(V600E) 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 patients with high-risk disease were analyzed. Two received conventional salvage chemotherapy, 4 patients on inhibitors were tracked at intervals of 3 to 6 years, and 10 patients, also given inhibitors, were analyzed more than 2 years after diagnosis. In contrast to the patients responding to salvage chemotherapy who completely cleared BRAF(V600E) within 6 months, children who received inhibitors maintained high BRAF(V600E) 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 peripheral blood mononuclear cells, more than 2 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 BRAF(V600E) 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.