Somatic activating ARAF mutations in Langerhans cell histiocytosis

被引：129

作者：

Nelson, David S. ^{[1
]}

Quispel, Willemijn ^{[2
]}

Badalian-Very, Gayane ^{[1
,3
,4
]}

van Halteren, Astrid G. S. ^{[2
]}

van den Bos, Cor ^{[5
]}

Bovee, Judith V. M. G. ^{[6
]}

Tian, Sara Y. ^{[1
]}

Van Hummelen, Paul ^{[7
]}

Ducar, Matthew ^{[7
]}

MacConaill, Laura E. ^{[4
,7
,8
]}

Egeler, R. Maarten ^{[9
]}

Rollins, Barrett J. ^{[1
,3
,4
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Leiden Univ, Willem Alexander Childrens Hosp, Med Ctr, Immunol Lab, Leiden, Netherlands

[3] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Boston, MA USA

[5] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, NL-1105 AZ Amsterdam, Netherlands

[6] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands

[7] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA

[8] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada

来源：

BLOOD | 2014年 / 123卷 / 20期

关键词：

ERDHEIM-CHESTER DISEASE; HUMAN CANCER; B-RAF; A-RAF; BRAF; ONCOGENE; KINASES;

D O I：

10.1182/blood-2013-06-511139

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：3152 / 3155

页数：4

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