Recurrent activating MAPK mutations in LCH. Known recurrent mutations in LCH are depicted. The majority of patients have mutually exclusive activating mutations in BRAF (BRAF-V600E) or MAP2K1. Individual cases of mutations in ARAF and ERBB3 have also been reported (*). In 15% to 40% of LCH lesions, no MAPK somatic mutations are identified. However, early series suggest ERK is activated in all cases of LCH. The dashed black line represents mechanisms of ERK activation outside of the MAPK pathway that remain to be defined. “Rx” represents steps in ERK activation that may be therapeutic targets. The red dashed line represents potential to target mechanisms outside of the MAPK pathway (eg, phosphatidylinositol 3-kinase/AKT) that may inhibit ERK activation by alternative pathways. The lightning bolt represents mechanisms downstream of ERK activation, that remain to be defined, that lead to LCH pathogenesis.