Wang Lin-na, Pan Qin, Fu Jian-fei, Shi Jing-yi, Jin Jie, Li Jun-ming, Hu Jiong, Zhao Wei-li, Chen Zhu, Chen Sai-juan
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Chin Med J (Engl). 2008 May 20;121(10):867-73.
The FIP1L1-PDGFRalpha fusion gene plays an important role in the pathogenesis of chronic eosinophilic leukemia (CEL) and is a direct therapeutic target of the tyrosine kinase inhibitor imatinib mesylate.
In 24 hypereosinophilic syndromes (HES) patients, using reverse transcriptase-polymerase chain reaction (RT-PCR), nested PCR and sequence analysis, we investigated the frequency of FIP1L1-PDGFRalpha and other abnormalities of tyrosine kinase family genes like PDGFRalpha, PDGFRbeta, C-KIT, FGFR1, ABL and FLT3 as well as gene mutation "hotspots", like MPL515 and JAK2V617F, frequently involved in myeloproliferative diseases. Fluorescence in situ hybridization was used to confirm the 4q12 deletion.
The FIP1L1-PDGFRalpha fusion transcript was found in 8 (33%) of 24 patients with HES, corresponding to the chromosome 4q12 deletion identified by FISH. The FIP1L1-PDGFRalpha-associated patients diagnosed with CEL, frequently had hepatosplenomegaly, eosinophil-related tissue damage, anemia, thrombocytopenia, myelofibrosis and a short overall survival time. Nevertheless, imatinib mesylate induced rapid and complete hematological responses in treated FIP1L1-PDGFRalpha cases, followed by molecular remission and reversal of myelofibrosis. FIP1L1-PDGFRalpha fusion could co-exist with other mutations of tyrosine kinase family genes, like FLT3 or PDGFRbeta. We also demonstrated that the SNPs of PDGFRbeta were associated with selective splicing of exon 19 in case 20.
Correlating the CEL genotype with phenotype, FIP1L1-PDGFRalpha emerges as a relatively homogeneous clinicobiological entity that co-exists with other abnormalities of tyrosine kinase family genes. It reflects the disease progression and there is a good response to imatinib. Detection of the FIP1L1-PDGFRalpha fusion gene is valid for both CEL diagnosis and therapy surveillance.
FIP1L1-PDGFRα融合基因在慢性嗜酸性粒细胞白血病（CEL）的发病机制中起重要作用，是酪氨酸激酶抑制剂甲磺酸伊马替尼的直接治疗靶点。
在24例高嗜酸性粒细胞综合征（HES）患者中，我们采用逆转录聚合酶链反应（RT-PCR）、巢式PCR和序列分析，研究FIP1L1-PDGFRα的频率以及酪氨酸激酶家族基因如PDGFRα、PDGFRβ、C-KIT、FGFR1、ABL和FLT3的其他异常情况，以及髓系增殖性疾病中常见的基因突变“热点”，如MPL515和JAK2V617F。采用荧光原位杂交技术确认4q12缺失。
在24例HES患者中有8例（33%）发现FIP1L1-PDGFRα融合转录本，与FISH检测到的4号染色体q12缺失相对应。诊断为CEL的FIP1L1-PDGFRα相关患者常伴有肝脾肿大、嗜酸性粒细胞相关组织损伤、贫血、血小板减少、骨髓纤维化和总生存时间短。然而，甲磺酸伊马替尼在治疗FIP1L1-PDGFRα病例中可诱导快速且完全的血液学反应，随后实现分子缓解和骨髓纤维化逆转。FIP1L1-PDGFRα融合可能与酪氨酸激酶家族基因的其他突变如FLT3或PDGFRβ共存。我们还证明，在病例20中，PDGFRβ的单核苷酸多态性与外显子19的选择性剪接有关。
将CEL基因型与表型相关联，FIP1L1-PDGFRα是一个相对同质的临床生物学实体，与酪氨酸激酶家族基因的其他异常共存。它反映了疾病进展，对伊马替尼有良好反应。检测FIP1L1-PDGFRα融合基因对CEL诊断和治疗监测均有效。
