Institute of Pathology, University Hospital Cologne, Kerpenerstrasse 62, 50924 Cologne, Germany.
Sci Transl Med. 2012 Jul 4;4(141):141ra91. doi: 10.1126/scitranslmed.3003967.
Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role of mutated ALK in tumorigenesis remains elusive. We demonstrate that targeted expression of the most frequent and aggressive variant, ALK(F1174L), is tumorigenic in mice. Tumors resembled human neuroblastomas in morphology, metastasis pattern, gene expression, and the presence of neurosecretory vesicles as well as synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated the genetic spectrum of the disease. Chromosomal aberrations were syntenic to those in human neuroblastoma, including 17q gain and MYCN oncogene amplification. Targeted ALK(F1174L) and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted. Treatment of ALK(F1174L) transgenic mice with the ALK inhibitor TAE-684 induced complete tumor regression, indicating that tumor cells were addicted to ALK(F1174L) activity. We conclude that an activating mutation within the ALK kinase domain is sufficient to induce neuroblastoma development, and ALK inhibitors show promise for treating human neuroblastomas harboring ALK mutations.
激活间变性淋巴瘤激酶（ALK）突变最近在大多数家族性和 10%的散发性神经母细胞瘤中被发现。然而，突变的 ALK 在肿瘤发生中的作用仍不清楚。我们证明，最常见和侵袭性变体 ALK(F1174L)的靶向表达在小鼠中具有致瘤性。肿瘤在形态、转移模式、基因表达以及神经分泌小泡和突触结构的存在方面与人类神经母细胞瘤相似。这种由 ALK 驱动的神经母细胞瘤小鼠模型精确地再现了疾病的遗传谱。染色体异常与人类神经母细胞瘤中的异常一致，包括 17q 增益和 MYCN 癌基因扩增。靶向 ALK(F1174L)和 MYCN 的共表达显示出在诱导神经母细胞瘤方面具有很强的协同作用，最小的染色体异常，这表明如果同时靶向两种癌蛋白，诱导肿瘤所需的次级打击更少。用 ALK 抑制剂 TAE-684 治疗 ALK(F1174L)转基因小鼠可诱导完全肿瘤消退，表明肿瘤细胞依赖于 ALK(F1174L)的活性。我们得出结论，ALK 激酶结构域内的激活突变足以诱导神经母细胞瘤的发生，ALK 抑制剂有望用于治疗携带 ALK 突变的人类神经母细胞瘤。
