Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas. Academic Article uri icon

Overview

abstract

  • Anaplastic large-cell lymphomas (ALCLs) carry chromosome translocations in which the anaplastic lymphoma kinase (ALK) gene is fused to several partners, most frequently, the NPM1 gene. We have demonstrated that the constitutive activation of ALK fusion proteins results in cellular transformation and lymphoid neoplasia. Herein, we specifically down-regulated ALK protein expression by using small hairpin RNA (shRNA) targeting a sequence coding for the catalytic domain of ALK. The ablation of ALK leads to the down-modulation of known ALK downstream effectors, cell growth arrest, and reversion of the transformed phenotype of ALK(+) mouse embryonic fibroblasts in vitro and in vivo. In human ALCL cells lentiviral-mediated ALK knock-down leads to G(1) cell-cycle arrest and apoptosis in vitro and tumor growth inhibition and regression in vivo. Using a specific approach we have demonstrated that the survival and growth of ALK(+) ALCLs are strictly dependent on ALK activation and signaling. Therefore, ALK is a viable target for therapeutic intervention and its inactivation might represent a pivotal approach for the treatment of ALK lymphomas and other ALK-dependent human tumors.

publication date

  • September 27, 2005

Research

keywords

  • Apoptosis
  • Lymphoma, Large-Cell, Anaplastic
  • Protein-Tyrosine Kinases
  • RNA Interference
  • RNA, Small Interfering

Identity

PubMed Central ID

  • PMC1895619

Scopus Document Identifier

  • 30444446194

Digital Object Identifier (DOI)

  • 10.1182/blood-2005-08-3254

PubMed ID

  • 16189272

Additional Document Info

volume

  • 107

issue

  • 2