Targeted expression of mutated ALK induces neuroblastoma in transgenic mice.

摘要: Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role mutated ALK tumorigenesis remains elusive. We demonstrate that targeted expression frequent aggressive variant, ALK(F1174L), is tumorigenic mice. Tumors resembled human neuroblastomas morphology, metastasis pattern, gene expression, presence neurosecretory vesicles as well synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated genetic spectrum disease. Chromosomal aberrations syntenic to those neuroblastoma, including 17q gain MYCN oncogene amplification. Targeted ALK(F1174L) coexpression revealed a strong synergism inducing with minimal chromosomal aberrations, suggesting fewer secondary hits are required for tumor induction if both oncoproteins targeted. Treatment transgenic mice inhibitor TAE-684 induced complete regression, indicating cells addicted activity. conclude an activating mutation within domain sufficient induce development, inhibitors show promise treating harboring mutations.