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Targeted expression of mutated ALK induces neuroblastoma in transgenic mice

Lukas C Heukamp1, Theresa Thor, Alexander Schramm

  • 1Institute of Pathology, University Hospital Cologne, Kerpenerstrasse 62, 50924 Cologne, Germany.

Science Translational Medicine
|July 6, 2012
PubMed

Insights

Activating anaplastic lymphoma kinase (ALK) mutations drive neuroblastoma development in mice, mimicking human disease. ALK inhibitors effectively regressed these tumors, showing promise for treating neuroblastoma patients with ALK mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Activating anaplastic lymphoma kinase (ALK) mutations are found in familial and sporadic neuroblastomas.
  • The precise role of mutated ALK in neuroblastoma tumorigenesis is not fully understood.

Purpose of the Study:

  • To investigate the tumorigenic potential of the aggressive ALK(F1174L) variant in a mouse model.
  • To characterize the resulting tumors and their genetic landscape.
  • To evaluate the efficacy of ALK inhibitors in treating ALK-driven neuroblastoma.

Main Methods:

  • Targeted expression of the ALK(F1174L) variant in mice.
  • Comparative analysis of tumor morphology, gene expression, and chromosomal aberrations with human neuroblastoma.
  • Coexpression studies with MYCN.
  • Treatment of transgenic mice with the ALK inhibitor TAE-684.

Main Results:

  • The ALK(F1174L) variant induced tumors resembling human neuroblastomas in mice, including metastasis and specific cellular structures.
  • The mouse model recapitulated the genetic spectrum of human neuroblastoma, with syntenic chromosomal aberrations.
  • Coexpression of ALK(F1174L) and MYCN synergistically induced neuroblastoma with fewer genetic alterations.
  • Treatment with TAE-684 led to complete tumor regression, demonstrating addiction to ALK activity.

Conclusions:

  • Activating mutations in the ALK kinase domain are sufficient for neuroblastoma induction.
  • ALK-driven neuroblastoma mouse models accurately reflect human disease characteristics.
  • Targeted therapy with ALK inhibitors holds significant therapeutic potential for neuroblastomas with ALK mutations.

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