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. 2012 Jul 4;4(141):141ra91.
doi: 10.1126/scitranslmed.3003967.

Targeted expression of mutated ALK induces neuroblastoma in transgenic mice

Lukas C Heukamp  1 , Theresa Thor, Alexander Schramm, Katleen De Preter, Candy Kumps, Bram De Wilde, Andrea Odersky, Martin Peifer, Sven Lindner, Annika Spruessel, Filip Pattyn, Pieter Mestdagh, Björn Menten, Steffi Kuhfittig-Kulle, Annette Künkele, Katharina König, Lydia Meder, Sampurna Chatterjee, Roland T Ullrich, Stefanie Schulte, Jo Vandesompele, Frank Speleman, Reinhard Büttner, Angelika Eggert, Johannes H Schulte
Affiliations

Targeted expression of mutated ALK induces neuroblastoma in transgenic mice

Lukas C Heukamp et al. Sci Transl Med. .

Abstract

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.

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