A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome
A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome
复制标题
DOI：
10.1056/nejmoa025217
复制
发表时间：
2003-03-27
影响因子：
158.5
通讯作者：
Gilliland, DG
中科院分区：
文献类型：
--
作者：
Cools, J;DeAngelo, DJ;Gilliland, DG
背景：特发性嗜酸性粒细胞增多综合征涉及与器官功能障碍相关的长期嗜酸性粒细胞增多状态。原因不明。最近的报告显示，伊马替尼的反应，如ABL，血小板源性生长因子受体（PDGFR），或KIT，所有这些都被抑制伊马替尼，可能是cause.METHODS：我们治疗了11例患者的高嗜酸性粒细胞综合征与伊马替尼和确定的分子基础的respons.RESULTS：9的11例患者伊马替尼治疗的反应持续超过三个月，其中嗜酸性粒细胞计数恢复正常。其中一名患者患有复杂的染色体异常，导致Fip 1样1（FIP 1 L1）基因与PDGFR（α）（PDGFRA）基因的融合，该融合由染色体4 q12上的间质缺失产生。FIP 1 L1-PDGFR（α）是一种组成型激活的酪氨酸激酶，可转化造血细胞，并被伊马替尼（50%抑制浓度，3.2 nM）抑制。FIP 1 L1-PDGFRA融合基因随后在16例综合征患者中的9例中检测到，并且在9例对伊马替尼反应持续超过3个月的患者中的5例中检测到。在一个病人的复发与PDGFRA的T674 I突变，赋予电阻imatinib.CONCLUSIONS：嗜酸性粒细胞增多综合征可能会导致从一个新的融合酪氨酸激酶-FIP 1 L1-PDGFR（α）-这是一个间质染色体缺失的后果的外观。在复发时获得T674 I耐药突变表明FIP 1 L1-PDGFR（α）是伊马替尼的靶点。我们的数据表明，遗传物质的缺失可能导致功能获得性融合蛋白。
BACKGROUND:Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.METHODS:We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.RESULTS:Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFR(alpha) (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFR(alpha) is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.CONCLUSIONS: The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFR(alpha) - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFR(alpha) is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.