Somatic activating ARAF mutations in Langerhans cell histiocytosis

• Published in: Blood 2014-05, Vol.123 (20), p.3152-3155
• Main Authors: Nelson, David S., Quispel, Willemijn, Badalian-Very, Gayane, van Halteren, Astrid G.S., van den Bos, Cor, Bovée, Judith V.M.G., Tian, Sara Y., Van Hummelen, Paul, Ducar, Matthew, MacConaill, Laura E., Egeler, R. Maarten, Rollins, Barrett J.
• Format: Article
• Language: English
• Subjects: Animals; BALB 3T3 Cells; Enzyme Activation; Histiocytosis, Langerhans-Cell - enzymology; Histiocytosis, Langerhans-Cell - genetics; Histiocytosis, Langerhans-Cell - pathology; Humans; Langerhans Cells - enzymology; Langerhans Cells - metabolism; Langerhans Cells - pathology; MAP Kinase Signaling System; Mice; Mutation; Proto-Oncogene Proteins A-raf - genetics; Proto-Oncogene Proteins B-raf - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-06-511139

The extracellular signal-regulated kinase (ERK) signaling pathway is activated in Langerhans cell histiocytosis (LCH) histiocytes, but only 60% of cases carry somatic activating mutations of BRAF. To identify other genetic causes of ERK pathway activation, we performed whole exome sequencing on purified LCH cells in 3 cases. One patient with wild-type BRAF alleles in his histiocytes had compound mutations in the kinase domain of ARAF. Unlike wild-type ARAF, this mutant was a highly active mitogen-activated protein kinase kinase in vitro and was capable of transforming mouse embryo fibroblasts. Mutant ARAF activity was inhibited by vemurafenib, a BRAF inhibitor, indicating the importance of fully evaluating ERK pathway abnormalities in selecting LCH patients for targeted inhibitor therapy. •Whole exome sequencing reveals novel mutations in ARAF that activate the kinase and are inhibitable by vemurafenib in a patient with LCH.•Requiring the presence of BRAF V600E in LCH to qualify for rat fibrosarcoma inhibitor treatment may be overly exclusionary.