在神经母细胞瘤中ALK激酶的致癌突变
Yuyan Chen1, Junko Takita, Young Lim Choi
1Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Nature
|October 17, 2008
概括
无性淋巴瘤激酶 (ALK) 改变在晚期神经母细胞瘤中很常见. 向突变ALK可能为这种难以治疗的儿科癌症提供新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 晚期神经母细胞瘤是一种具有挑战性的儿科癌症,治疗目标有限.
- 已知的遗传改变包括MYCN放大和染色体损失/增益.
- 有效治疗方法的开发受到可靠分子点的稀缺性所阻碍.
研究的目的:
- 研究形淋巴瘤激酶 (ALK) 作为高级神经母细胞瘤中潜在的治疗点的作用.
- 在神经母细胞瘤样本中的ALK基因中识别遗传变化,包括拷贝数变化和突变.
主要方法:
- 在215个初级神经母细胞瘤样本上使用高密度单核酸多态基因定型微阵列进行全基因组扫描.
- 在初级瘤和神经母细胞瘤衍生的细胞系中,ALK基因的DNA测序.
- 功能性研究包括酶活性测定,NIH3T3纤维细胞转化和RNA干扰介导的ALK下调.
主要成果:
- ALK位点被确定为复制数增长和扩大在晚期神经母细胞瘤中反复出现的目标.
- 在ALK激酶域中发现了8种新的误解突变,在6.1%的原发性瘤 (第3至第4阶段) 和33%的细胞系中发现.
- 突变的ALK激酶表现出增加的自酸化和激酶活性,转化NIH3T3细胞并形成小鼠中的瘤.
- 降低ALK的调节抑制了ALK突变的神经母细胞瘤细胞中的增殖.
结论:
- 无细胞淋巴瘤激酶 (ALK) 在晚期神经母细胞瘤中经常发生变化,这表明它参与了疾病的发病.
- 在ALK中的突变赋予了致癌活性,并代表了潜在的治疗点.
- 特定于ALK的激酶抑制剂有望改善ALK变化的神经母细胞瘤患者的临床结果.
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