Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia.
Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia.
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DOI：
10.1182/blood.v98.8.2518
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发表时间：
2001-10
期刊：
影响因子：
20.3
通讯作者：
M. K. Magnússon;K. Meade;K. E. Brown;D. Arthur;Lisa A. Krueger;A. Barrett;C. Dunbar
中科院分区：
文献类型：
--
作者：
M. K. Magnússon;K. Meade;K. E. Brown;D. Arthur;Lisa A. Krueger;A. Barrett;C. Dunbar
在一些慢性粒单核细胞白血病（CMML）患者中已报告涉及血小板衍生生长因子β受体（PDGF β R）基因的染色体易位。所得融合蛋白具有组成型PDGF β R酪氨酸激酶活性，但先前报道的伴侣基因（tel，亨廷顿相互作用蛋白1 [HIP-1]，H4/D10 S170）在融合蛋白的致癌活性中的作用知之甚少。一种新的PDGFbetaR融合蛋白已在CMML和获得性t（5;17）（q33;p13）患者中得到表征。对患者白血病细胞的Southern印迹分析证明了PDGFbetaR基因的参与。使用5'互补DNA末端快速扩增-聚合酶链反应（RACE-PCR）对患者RNA，rabaptin-5被鉴定为与PDGF β R基因框内融合的新伴侣。新的融合蛋白包括超过85%的天然Rabaptin-5融合到PDGF β R的跨膜和细胞内酪氨酸激酶结构域。用表达rabaptin-5/PDGFbetaR的逆转录病毒载体转导，使造血细胞系Ba/F3转化为生长因子非依赖性，并在小鼠中引起致命的骨髓增生性疾病。Rabaptin-5是一种经过充分研究的蛋白质，显示其通过与Ras家族GTP酶Rab 5和Rab 4相互作用而成为早期内体融合的必需和限速组分。融合蛋白包括4个卷曲螺旋结构域中的3个（参与天然rabaptin-5的同源二聚化）、2个半胱天冬酶-3切割位点和肿瘤抑制基因tuberin（结节性硬化症复合物-2）的结合位点。早期内体转运通过配体诱导的网格蛋白介导的内吞作用在各种生长因子受体的调节中至关重要，因此这种新的融合蛋白将生长调节的2个重要途径连接在一起。
Chromosomal translocations involving the platelet-derived growth factor beta receptor (PDGFbetaR) gene have been reported in some patients with chronic myelomonocytic leukemia (CMML). The resultant fusion proteins have constitutive PDGFbetaR tyrosine kinase activity, but the partner genes previously reported (tel, Huntingtin interacting protein 1 [HIP-1], H4/D10S170) have poorly understood roles in the oncogenic activity of the fusion proteins. A novel PDGFbetaR fusion protein has been characterized in a patient with CMML and an acquired t(5;17)(q33;p13). Southern blot analysis on patient leukemia cells demonstrated involvement of the PDGFbetaR gene. Using 5' rapid amplification of complementary DNA ends-polymerase chain reaction (RACE-PCR) on patient RNA, rabaptin-5 was identified as a novel partner fused in-frame to the PDGFbetaR gene. The new fusion protein includes more than 85% of the native Rabaptin-5 fused to the transmembrane and intracellular tyrosine kinase domains of the PDGFbetaR. Transduction with a retroviral vector expressing rabaptin-5/PDGFbetaR transformed the hematopoietic cell line Ba/F3 to growth factor independence and caused a fatal myeloproliferative disease in mice. Rabaptin-5 is a well-studied protein shown to be an essential and rate-limiting component of early endosomal fusion through interaction with the Ras family GTPases Rab5 and Rab4. The fusion protein includes 3 of 4 coiled-coil domains (involved in homodimerization of native rabaptin-5), 2 caspase-3 cleavage sites, and a binding site for the tumor suppressor gene tuberin (tuberous sclerosis complex-2). Early endosomal transport is critical in regulation of various growth factor receptors, through ligand-induced clathrin-mediated endocytosis, and thus this new fusion protein links together 2 important pathways of growth regulation.