title: Somatic activating ARAF mutations in Langerhans cell histiocytosis.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: David S
authors.initials: DS
authors.lastname: Nelson
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Willemijn
authors.initials: W
authors.lastname: Quispel
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA;
authors.forename: Gayane
authors.initials: G
authors.lastname: Badalian-Very
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Astrid G S
authors.initials: AG
authors.lastname: van Halteren
authors.affiliation: Emma Childrens Hospital/Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Cor
authors.initials: C
authors.lastname: van den Bos
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Sara Y
authors.initials: SY
authors.lastname: Tian
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hummelen
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Matthew
authors.initials: M
authors.lastname: Ducar
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA; Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA; and.
authors.forename: Laura E
authors.initials: LE
authors.lastname: MacConaill
authors.affiliation: Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA;
authors.forename: Barrett J
authors.initials: BJ
authors.lastname: Rollins
mesh_terms: D000818:Animals; D041702:BALB 3T3 Cells; D004789:Enzyme Activation; D006646:Histiocytosis, Langerhans-Cell / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007801:Langerhans Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf