TY - JOUR
T1 - Somatic activating ARAF mutations in Langerhans cell histiocytosis
AU - Nelson, David S.
AU - Quispel, Willemijn
AU - Badalian-Very, Gayane
AU - van Halteren, Astrid G. S.
AU - van den Bos, Cor
AU - Bovée, Judith V. M. G.
AU - Tian, Sara Y.
AU - van Hummelen, Paul
AU - Ducar, Matthew
AU - MacConaill, Laura E.
AU - Egeler, R. Maarten
AU - Rollins, Barrett J.
PY - 2014
Y1 - 2014
N2 - 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
AB - 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
U2 - https://doi.org/10.1182/blood-2013-06-511139
DO - https://doi.org/10.1182/blood-2013-06-511139
M3 - Article
C2 - 24652991
SN - 0006-4971
VL - 123
SP - 3152
EP - 3155
JO - Blood
JF - Blood
IS - 20
ER -