The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management.
The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management.
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发表时间：
2004
期刊：
影响因子：
20.3
通讯作者：
J. Gotlib;J. Cools;J. Malone;S. Schrier;D. Gilliland;S. Coutre
中科院分区：
文献类型：
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作者：
J. Gotlib;J. Cools;J. Malone;S. Schrier;D. Gilliland;S. Coutre
特发性嗜酸性粒细胞增多综合征 (HES) 和慢性嗜酸性粒细胞白血病 (CEL) 包括一系列惰性至侵袭性疾病，其特征是无法解释的持续性嗜酸性粒细胞增多。这些疾病一直没有找到独特的分子解释，治疗主要是为了缓解与器官受累相关的症状。最近的报告表明，HES 和 CEL 是伊马替尼反应性恶性肿瘤，与慢性粒细胞白血病 (CML) 相比，在较低剂量下即可观察到快速且完全的血液学缓解。这些 BCR-ABL 阴性病例缺乏涉及伊马替尼其他已知靶基因的激活突变或异常融合，表明其发病机制中存在一种新型酪氨酸激酶。一项床边到台式的转化研究工作导致在染色体 4q12 上鉴定出一种组成型激活的融合酪氨酸激酶，该激酶源自间质缺失，它将血小板衍生生长因子受体-α 基因 (PDGFRA) 与未表征的人类基因 FIP1-like-1 (FIP1L1) 融合。然而，并非所有 HES 和 CEL 患者都对伊马替尼有反应，表明疾病异质性。此外，大约 40% 的有反应患者缺乏 FIP1L1-PDGFRA 融合，表明遗传异质性。本综述探讨了 HES 和 CEL 的当前知识状况以及 FIP1L1-PDGFRA 的发现对其诊断、分类和管理的影响。
Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.