title: Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms.
abstract: Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.
  
  
  CONCLUSIONS
  We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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authors.affiliation: Genome Technology Center, NYU Langone Medical Center, New York, New York.
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authors.affiliation: Genome Technology Center, NYU Langone Medical Center, New York, New York.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D020869:Gene Expression Profiling / Q000379:methods*; D006646:Histiocytosis, Langerhans-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D015616:Histiocytosis, Non-Langerhans-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020917:Receptor, trkA / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human