The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice.
The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice.
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Tel-PDGFRbeta 融合基因在转基因小鼠中产生慢性骨髓增殖综合征。
DOI：
10.1038/sj.leu.2401494
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发表时间：
1999
期刊：
影响因子：
11.4
通讯作者：
Hickstein,DD
中科院分区：
文献类型：
--
作者：
Ritchie,KA;Aprikyan,AA;Bowen-Pope,DF;Norby-Slycord,CJ;Conyers,S;Bartelmez,S;Sitnicka,EH;Hickstein,DD
慢性髓细胞白血病（CMML）是一种白血病前期综合征，表现为骨髓增生异常和骨髓增生性特征。t（5; 12）染色体易位存在于骨髓增生的CMML患者亚群中，将ets家族成员Tel的氨基末端部分与血小板衍生生长因子受体β (PDGFRβ)基因的跨膜和酪氨酸激酶结构域融合在一起。为了研究该融合蛋白在CMML发病机制中的作用，我们在人CD11a启动子的控制下，在转基因小鼠的造血细胞中表达了Tel-PDGFRβ融合cDNA。转基因创始人及其后代在造血组织中特异性表达转基因，并产生骨髓增生综合征，其特征是：骨髓中成熟中性粒细胞和巨核细胞过量产生；脾肿大伴髓外造血脾结构消失；共同表达淋巴细胞和髓细胞标记物的异常白细胞群；体外骨髓CFU检测中菌落数量增加。所有表达转基因的小鼠都表现出至少一种骨髓生成失调的特征，20%的小鼠进展为骨髓或淋巴细胞恶性肿瘤。这种小鼠CMML模型与人类的骨髓增生性综合征相似，并暗示Tel-PDGFRβ融合蛋白在其发病机制中起作用。
Chronic myelomonocytic leukemia (CMML) is a pre-leukemic syndrome that displays both myelodysplastic and myeloproliferative features. The t (5; 12) chromosomal translocation, present in a subset of CMML patients with myeloproliferation fuses the amino terminal portion of the ets family member, Tel, with the transmembrane and tyrosine kinase domains of platelet-derived growth factor receptor β (PDGFRβ) gene. To investigate the role of this fusion protein in the pathogenesis of CMML, we expressed the Tel-PDGFRβ fusion cDNA in hematopoietic cells of transgenic mice under the control of the human CD11a promoter. Transgenic founders and their offspring express the transgene specifically in hematopoietic tissues and develop a myeloproliferative syndrome characterized by: overproduction of mature neutrophils and megakaryocytes in the bone marrow; splenomegaly with effacement of splenic architecture by extramedullary hematopoiesis; an abnormal population of leukocytes co-expressing lymphoid and myeloid markers; and increased numbers of colonies in in vitro bone marrow CFU assays. All mice expressing the transgene exhibited at least one of these features of dysregulated myelopoiesis, and 20% progressed to a myeloid or lymphoid malignancy. This murine model of CMML parallels a myeloproliferative syndrome in humans and implicates the Tel-PDGFRβ fusion protein in its pathogenesis.