Somatic mutations in ARAF and MAP2K1, activating the RAS-RAF-MEK-ERK pathway [45] or the over-expression of p16(INK4a) and p21(CIP1/WAF1) [51] in the absence of a BRAF mutation in LCH, should polarize further investigation in order to develop more effective targeted therapies. This evidence concerns the gene CDKN1A and Langerhans cell histiocytosis.