Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis

Shizhen Zhu, Jeong Soo Lee, Feng Guo, Jimann Shin, Antonio R. Perez-Atayde, Jeffery L. Kutok, Scott J. Rodig, Donna S. Neuberg, Daniel Helman, Hui Feng, Rodney A. Stewart, Wenchao Wang, Rani E. George, John P. Kanki, A. Thomas Look

Research output: Contribution to journalArticle

169 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)362-373
Number of pages12
JournalCancer cell
Volume21
Issue number3
DOIs
StatePublished - Mar 20 2012

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Zhu, S., Lee, J. S., Guo, F., Shin, J., Perez-Atayde, A. R., Kutok, J. L., Rodig, S. J., Neuberg, D. S., Helman, D., Feng, H., Stewart, R. A., Wang, W., George, R. E., Kanki, J. P., & Look, A. T. (2012). Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis. Cancer cell, 21(3), 362-373. https://doi.org/10.1016/j.ccr.2012.02.010