title: Targeted expression of mutated ALK induces neuroblastoma in transgenic mice.
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.
authors: Institute of Pathology, University Hospital Cologne, Kerpenerstrasse 62, 50924 Cologne, Germany.
authors: Lukas C
authors: LC
authors: Heukamp
authors: Theresa
authors: T
authors: Thor
authors: Alexander
authors: A
authors: Schramm
authors: Katleen
authors: K
authors: De Preter
authors: Candy
authors: C
authors: Kumps
authors: Bram
authors: B
authors: De Wilde
authors: Andrea
authors: A
authors: Odersky
authors: Martin
authors: M
authors: Peifer
authors: Sven
authors: S
authors: Lindner
authors: Annika
authors: A
authors: Spruessel
authors: Filip
authors: F
authors: Pattyn
authors: Pieter
authors: P
authors: Mestdagh
authors: Björn
authors: B
authors: Menten
authors: Steffi
authors: S
authors: Kuhfittig-Kulle
authors: Annette
authors: A
authors: Künkele
authors: Katharina
authors: K
authors: König
authors: Lydia
authors: L
authors: Meder
authors: Sampurna
authors: S
authors: Chatterjee
authors: Roland T
authors: RT
authors: Ullrich
authors: Stefanie
authors: S
authors: Schulte
authors: Jo
authors: J
authors: Vandesompele
authors: Frank
authors: F
authors: Speleman
authors: Reinhard
authors: R
authors: Büttner
authors: Angelika
authors: A
authors: Eggert
authors: Johannes H
authors: JH
authors: Schulte
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C516714:NVP-TAE684; D011743:Pyrimidines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases