在神经母细胞瘤中ALK激酶受体的体和生殖线激活突变
Isabelle Janoueix-Lerosey1, Delphine Lequin, Laurence Brugières
1Institut Curie, Centre de Recherche, and Inserm, U830, 26 rue d'Ulm, Paris F-75248, France.
无细胞淋巴瘤激酶 (ALK) 基因放大和突变是神经母细胞瘤的关键驱动因素,这是一个常见的儿童癌症. 准ALK为这种常常致命的疾病提供了一个有希望的治疗策略.
科学领域:
- 在瘤学瘤学.
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 神经母细胞瘤是一种常见的儿童固体瘤,起源于外周交感神经系统.
- 虽然经常是零星的,但家族病例和与先天性形的关联表明遗传基础.
研究的目的:
- 研究神经母细胞瘤中的遗传变化,重点关注瘤发展的潜在驱动因素.
- 为了确定神经母细胞瘤治疗的新型治疗点.
主要方法:
- 全基因组比较基因组杂交 (CGH) 在大量神经母细胞瘤上进行.
- 在细胞系和原发性瘤中直接测序ALK激酶域.
- 功能性研究包括基因淘汰和蛋白质活性测试.
主要成果:
- 鉴定出在性淋巴瘤激酶 (ALK) 位点的复发性拷贝数增加.
- 在神经母细胞瘤样本中发现了ALK激酶域内的体质突变.
- 在家族性神经母细胞瘤病例中观察到生殖系ALK突变,确定ALK是一种倾向基因.
- 突变的ALK蛋白表现出过度表达,高酸化和构成性激酶活性.
- 抑制ALK显著降低了神经母细胞瘤细胞的增殖,无论突变状态如何.
结论:
- 在神经母细胞瘤的发展中,ALK是关键的瘤驱动因素.
- ALK是神经母细胞瘤的重要治疗点,该疾病目前治疗选择有限.
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