Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis

Rikhia Chakraborty, Oliver A. Hampton, Xiaoyun Shen, Stephen J. Simko, Albert Shih, Harshal Abhyankar, Karen Phaik Har Lim, Kyle R. Covington, Lisa Trevino, Ninad Dewal, Donna M. Muzny, Harshavardhan Doddapaneni, Jianhong Hu, Linghua Wang, Philip J. Lupo, M. John Hicks, Diana L. Bonilla, Karen C. Dwyer, Marie Luise Berres, Poulikos I. PoulikakosMiriam Merad, Kenneth L. McClain, David A. Wheeler, Carl E. Allen, D. Williams Parsons

Research output: Contribution to journalArticlepeer-review

Abstract

Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder characterized by lesions composed of pathological CD207+ dendritic cells with an inflammatory infiltrate. BRAFV600E remains the only recurrent mutation reported in LCH. In order to evaluate the spectrum of somatic mutations in LCH, whole exome sequencing was performed on matched LCH and normal tissue samples obtained from 41 patients. Lesions from other histiocytic disorders, juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease were also evaluated. All of the lesions from histiocytic disorders were characterized by an extremely low overall rate of somatic mutations. Notably, 33% (7/21) of LCH cases with wild-type BRAF and none (0/20) with BRAFV600E harbored somatic mutations in MAP2K1 (6 in-frame deletions and 1 missense mutation) that induced extracellular signal-regulated kinase (ERK) phosphorylation in vitro. Single cases of somatic mutations of the mitogen-activated protein kinase (MAPK) pathway genes ARAF and ERBB3 were also detected. The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in cell culture and primary tumor models was dependent on the specific LCH mutation. The findings of this study support a model in which ERK activation is a universal end point in LCH arising from pathological activation of up stream signaling proteins.

Original languageEnglish (US)
Pages (from-to)3007-3015
Number of pages9
JournalBlood
Volume124
Issue number19
DOIs
StatePublished - Nov 6 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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