Somatic activating ARAF mutations in Langerhans cell histiocytosis

David S. Nelson, Willemijn Quispel, Gayane Badalian-Very, Astrid G.S. Van Halteren, Cor Den Van Bos, Judith V.M.G. Bovée, Sara Y. Tian, Paul Van Hummelen, Matthew Ducar, Laura E. MacConaill, R. Maarten Egeler, Barrett J. Rollins

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

139 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)3152-3155
Aantal pagina's4
TijdschriftBlood
Volume123
Nummer van het tijdschrift20
DOI's
StatusGepubliceerd - 15 mei 2014
Extern gepubliceerdJa

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