Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms. Academic Article uri icon

Overview

abstract

  • UNLABELLED: 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. SIGNIFICANCE: 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

  • Diamond, Eli L.
  • Durham, Benjamin H
  • Haroche, Julien
  • Yao, Zhan
  • Ma, Jing
  • Parikh, Sameer A
  • Wang, Zhaoming
  • Choi, John
  • Kim, Eunhee
  • Cohen-Aubart, Fleur
  • Lee, Stanley Chun-Wei
  • Gao, Yijun
  • Micol, Jean-Baptiste
  • Campbell, Patrick
  • Walsh, Michael P
  • Sylvester, Brooke
  • Dolgalev, Igor
  • Aminova, Olga
  • Heguy, Adriana
  • Zappile, Paul
  • Nakitandwe, Joy
  • Ganzel, Chezi
  • Dalton, James D
  • Ellison, David W
  • Estrada-Veras, Juvianee
  • Lacouture, Mario
  • Gahl, William A
  • Stephens, Philip J
  • Miller, Vincent A
  • Ross, Jeffrey S
  • Ali, Siraj M
  • Briggs, Samuel R
  • Fasan, Omotayo
  • Block, Jared
  • Héritier, Sebastien
  • Donadieu, Jean
  • Solit, David
  • Hyman, David M
  • Baselga, José
  • Janku, Filip
  • Taylor, Barry S
  • Park, Christopher Y
  • Amoura, Zahir
  • Dogan, Ahmet
  • Emile, Jean-Francois
  • Rosen, Neal
  • Gruber, Tanja A
  • Abdel-wahab, Omar

publication date

  • November 13, 2015

Research

keywords

  • Gene Expression Profiling
  • Histiocytosis, Langerhans-Cell
  • Histiocytosis, Non-Langerhans-Cell
  • Mutation
  • Sequence Analysis, DNA

Identity

PubMed Central ID

  • PMC4744547

Scopus Document Identifier

  • 84957056573

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-15-0913

PubMed ID

  • 26566875

Additional Document Info

volume

  • 6

issue

  • 2