Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis
Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis
复制标题
DOI：
10.1182/blood-2014-05-577825
复制
发表时间：
2014-11-06
期刊：
影响因子：
20.3
通讯作者：
Parsons, D. Williams
中科院分区：
文献类型：
--
作者：
Chakraborty, Rikhia;Hampton, Oliver A.;Parsons, D. Williams
朗格汉斯细胞组织细胞增生症（LCH）是一种骨髓增生性疾病，其特征是病变由病理性CD 207（+）树突状细胞和炎性浸润组成。BRAFV 600 E仍然是LCH中报告的唯一复发性突变。为了评估LCH中的体细胞突变谱，对从41名患者获得的匹配的LCH和正常组织样品进行全外显子组测序。还评价了其他组织细胞疾病、青少年黄色肉芽肿、Erdheim-Chester病和Rosai-Dorfman病的病变。组织细胞疾病的所有病变的特征是体细胞突变的总体发生率极低。值得注意的是，33%（7/21）的野生型BRAF LCH病例和0例（0/20）BRAFV 600 E LCH病例在体外诱导细胞外信号调节激酶（ERK）磷酸化的MAP 2K 1中携带体细胞突变（6个框内缺失和1个错义突变）。还检测到丝裂原活化蛋白激酶（MAPK）途径基因ARAF和ERBB 3的单个体细胞突变病例。MAPK通路抑制剂在细胞培养和原发性肿瘤模型中抑制MAPK激酶和ERK磷酸化的能力依赖于特异性LCH突变。这项研究的结果支持了一个模型，其中ERK激活是一个普遍的终点LCH所产生的病理激活的上游信号蛋白。
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 ERBB3were also detected. The ability ofMAPKpathway 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 upstream signaling proteins.