The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies.
In this issue of Blood, Nelson et al describe a novel somatic ARAF mutation in a child with Langerhans cell histiocytosis (LCH) and demonstrate that the encoded protein has strong gain-of-function properties.