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

155 Citations (Scopus)

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
Externally publishedYes

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Neuroblastoma
Chromaffin Cells
Adrenal Medulla
Organogenesis
Penetrance
Zebrafish
Oncogenes
Hyperplasia
Cell Differentiation
Neoplasms
anaplastic lymphoma kinase

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., ... 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

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

In: Cancer Cell, Vol. 21, No. 3, 20.03.2012, p. 362-373.

Research output: Contribution to journalArticle

Zhu, S, Lee, JS, Guo, F, Shin, J, Perez-Atayde, AR, Kutok, JL, Rodig, SJ, Neuberg, DS, Helman, D, Feng, H, Stewart, RA, Wang, W, George, RE, Kanki, JP & Look, AT 2012, 'Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis', Cancer Cell, vol. 21, no. 3, pp. 362-373. https://doi.org/10.1016/j.ccr.2012.02.010
Zhu S, Lee JS, Guo F, Shin J, Perez-Atayde AR, Kutok JL et al. Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis. Cancer Cell. 2012 Mar 20;21(3):362-373. https://doi.org/10.1016/j.ccr.2012.02.010
Zhu, Shizhen ; Lee, Jeong Soo ; Guo, Feng ; Shin, Jimann ; Perez-Atayde, Antonio R. ; Kutok, Jeffery L. ; Rodig, Scott J. ; Neuberg, Donna S. ; Helman, Daniel ; Feng, Hui ; Stewart, Rodney A. ; Wang, Wenchao ; George, Rani E. ; Kanki, John P. ; Look, A. Thomas. / Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis. In: Cancer Cell. 2012 ; Vol. 21, No. 3. pp. 362-373.
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