Durham Benjamin H, Diamond Eli L, Abdel-Wahab Omar
aDepartment of Pathology bDepartment of Neurology cHuman Oncology and Pathogenesis Program dLeukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Curr Opin Hematol. 2016 Jul;23(4):416-25. doi: 10.1097/MOH.0000000000000256.
Since the discovery of B-Raf proto-oncogene (BRAF) V600E mutations in histiocytic neoplasms, diverse kinase alterations have been uncovered in BRAF V600E-wildtype histiocytoses. The purpose of this review is to outline recent molecular advances in histiocytic neoplasms and discuss their impact on the pathogenesis and treatment of these disorders.
Activating kinase alterations discovered in BRAF V600E-wildtype Langerhans (LCH) and non-Langerhans cell histiocytoses (non-LCH) result in constitutive activation of the mitogen-activated protein kinase and/or phosphoinositide 3-kinases-Akt murine thymoma pathways. These kinase alterations include activating mutations in A-Raf proto-oncogene, mitogen-activated protein kinase kinase 1, neuroblastoma rat sarcoma viral oncogene homolog, Kirsten rat sarcoma viral oncogene homolog, and phosphatidylinositol-4,5-bisphosphate 3 kinase, catalytic subunit α kinases in LCH and non-LCH; BRAF, anaplastic lymphoma receptor tyrosine kinase, and neurotrophic tyrosine kinase, receptor type 1 fusions, as well as the Ets variant 3-nuclear receptor coactivator 2 fusion in non-LCH; and mutations in the mitogen-activated protein kinase kinase kinase 1 and Harvey rat sarcoma viral oncogene homolog kinases in LCH and histiocytic sarcoma, respectively. These discoveries have refined the understanding of the histiocytoses as clonal, myeloid neoplasms driven by constitutive mitogen-activated protein kinase signaling and identified molecular therapeutic targets with promising clinical responses to rapidly accelerated fibrosarcoma and mitogen-activated protein kinase kinase inhibition.
Genomic analyses over the last 6 years have identified targetable kinase alterations in BRAF V600E-wildtype histiocytic neoplasms. However, despite this progress, the molecular pathogenesis and therapeutic responsiveness of non-BRAF V600E kinase alterations are still poorly defined in these disorders.
自从在组织细胞肿瘤中发现B-Raf原癌基因（BRAF）V600E突变以来，在BRAF V600E野生型组织细胞增多症中发现了多种激酶改变。本综述的目的是概述组织细胞肿瘤最近的分子进展，并讨论它们对这些疾病的发病机制和治疗的影响。
在BRAF V600E野生型朗格汉斯细胞组织细胞增多症（LCH）和非朗格汉斯细胞组织细胞增多症（非LCH）中发现的激活激酶改变导致丝裂原活化蛋白激酶和/或磷酸肌醇3激酶-Akt鼠胸腺瘤途径的组成性激活。这些激酶改变包括A-Raf原癌基因、丝裂原活化蛋白激酶激酶1、神经母细胞瘤鼠肉瘤病毒癌基因同源物、 Kirsten鼠肉瘤病毒癌基因同源物以及磷脂酰肌醇-4,5-二磷酸3激酶催化亚基α激酶在LCH和非LCH中的激活突变；BRAF、间变性淋巴瘤受体酪氨酸激酶和神经营养酪氨酸激酶受体1型融合，以及非LCH中的Ets变体3-核受体辅激活因子2融合；丝裂原活化蛋白激酶激酶激酶1和Harvey鼠肉瘤病毒癌基因同源激酶分别在LCH和组织细胞肉瘤中的突变。这些发现深化了对组织细胞增多症作为由组成性丝裂原活化蛋白激酶信号驱动的克隆性髓系肿瘤的理解，并确定了对快速进展性纤维肉瘤和丝裂原活化蛋白激酶激酶抑制有良好临床反应的分子治疗靶点。
过去6年的基因组分析已经在BRAF V600E野生型组织细胞肿瘤中确定了可靶向的激酶改变。然而，尽管取得了这一进展，但在这些疾病中，非BRAF V600E激酶改变的分子发病机制和治疗反应性仍不清楚。
