title: Activated ALK collaborates with MYCN in neuroblastoma pathogenesis.
abstract: Amplification of the MYCN oncogene in childhood neuroblastoma is often accompanied by mutational activation of ALK (anaplastic lymphoma kinase), suggesting their pathogenic cooperation. We generated a transgenic zebrafish model of neuroblastoma in which MYCN-induced tumors arise from a subpopulation of neuroblasts that migrate into the adrenal medulla analog following organogenesis. Coexpression of activated ALK with MYCN in this model triples the disease penetrance and markedly accelerates tumor onset. MYCN overexpression induces adrenal sympathetic neuroblast hyperplasia, blocks chromaffin cell differentiation, and ultimately triggers a developmentally-timed apoptotic response in the hyperplastic sympathoadrenal cells. Coexpression of activated ALK with MYCN provides prosurvival signals that block this apoptotic response and allow continued expansion and oncogenic transformation of hyperplastic neuroblasts, thus promoting progression to neuroblastoma.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shizhen
authors.initials: S
authors.lastname: Zhu
authors.forename: Jeong-Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.forename: Jimann
authors.initials: J
authors.lastname: Shin
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Daniel
authors.initials: D
authors.lastname: Helman
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Stewart
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.forename: Rani E
authors.initials: RE
authors.lastname: George
authors.forename: John P
authors.initials: JP
authors.lastname: Kanki
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D006801:Humans; D008969:Molecular Sequence Data; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D030781:Organisms, Genetically Modified; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015027:Zebrafish / Q000235:genetics*
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases