ALK Rearrangement in Sickle Cell Trait-Associated Renal Medullary Carcinoma
ALK Rearrangement in Sickle Cell Trait-Associated Renal Medullary Carcinoma
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DOI：
10.1002/gcc.20839
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发表时间：
2011-03-01
影响因子：
3.7
通讯作者：
Perez-Atayde, Antonio R.
中科院分区：
文献类型：
--
作者：
Marino-Enriquez, Adrian;Ou, Wen-Bin;Perez-Atayde, Antonio R.
肾髓质癌 (RMC) 是一种侵袭性恶性肿瘤，影响具有镰状细胞特征的年轻黑人。没有有效的治疗方法，导致临床病程不祥，总生存期平均不到四个月。我们报告在一例携带 t(2;10)(p23;q22) 易位的 RMC 儿科病例中发现 ALK 受体酪氨酸激酶重排。基于质谱的蛋白质组学评估鉴定出一种新型 ALK 癌蛋白，其中细胞骨架蛋白纽蛋白 (VCL) 与 ALK 激酶结构域融合。所得的 VCL-ALK 融合不包含已知的自关联结构域，但包含纽蛋白的踝蛋白结合结构域。我们证明了强酪氨酸磷酸化的踝蛋白与 VCL-ALK 癌蛋白的共沉淀，表明 ALK 致癌交叉磷酸化是通过踝蛋白支架上相邻 VCL-ALK 蛋白之间的相互作用介导的。该报告拓宽了 ALK 相关肿瘤和 ALK 融合伴侣的范围。并提供了使用靶向 ALK 抑制剂治疗 RMC 的基本原理。 (C) 2010 Wiley-Liss, Inc.
Renal Medullary Carcinoma (RMC) is an aggressive malignancy that affects young black individuals with sickle cell trait. No effective treatment is available, resulting in an ominous clinical course, with overall survival averaging less than four months. We report rearrangement of the ALK receptor tyrosine kinase in a pediatric case of RMC harboring a t(2;10)(p23;q22) translocation. Mass spectrometry-based proteomic evaluation identified a novel ALK oncoprotein in which the cytoskeletal protein vinculin (VCL) was fused to the ALK kinase domain. The resulting VCL-ALK fusion does not contain known self-association domains, but includes the talin binding domains of vinculin. We demonstrate coprecipitation of strongly tyrosine phosphorylated talins with the VCL-ALK oncoprotein, suggesting that ALK oncogenic crossphosphorylation is mediated by interactions between neighboring VCL-ALK proteins on a talin scaffold. This report widens the spectrum of ALK-related tumors and ALK fusion partners. and provides a rationale for treating RMC with targeted ALK inhibitors. (C) 2010 Wiley-Liss, Inc.