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Activated ALK collaborates with MYCN in neuroblastoma pathogenesis.

Cancer cell | Mar 20, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22439933

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.

Pubmed ID: 22439933 RIS Download

Mesh terms: Animals | Cell Differentiation | Disease Models, Animal | Humans | Molecular Sequence Data | Neuroblastoma | Nuclear Proteins | Oncogene Proteins | Organisms, Genetically Modified | Receptor Protein-Tyrosine Kinases | Zebrafish

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Associated grants

  • Agency: NCI NIH HHS, Id: CA104605
  • Agency: NCI NIH HHS, Id: K99CA134743
  • Agency: NCI NIH HHS, Id: R00 CA134743
  • Agency: NINDS NIH HHS, Id: R00 NS058608
  • Agency: NINDS NIH HHS, Id: R00 NS058608
  • Agency: NCI NIH HHS, Id: R01 CA104605
  • Agency: NCI NIH HHS, Id: R01 CA104605-04
  • Agency: NCI NIH HHS, Id: R01 CA148688

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