Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas

• Published in: Blood 2006-01, Vol.107 (2), p.689-697
• Main Authors: Piva, Roberto, Chiarle, Roberto, Manazza, Andrea D., Taulli, Riccardo, Simmons, William, Ambrogio, Chiara, D'Escamard, Valentina, Pellegrino, Elisa, Ponzetto, Carola, Palestro, Giorgio, Inghirami, Giorgio
• Format: Article
• Language: English
• Subjects: Anaplastic Lymphoma Kinase; Animals; Apoptosis; Biological and medical sciences; Cell Cycle; Cell Proliferation; Cell Transformation, Neoplastic; Fibroblasts; Fluorescent Antibody Technique; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Large-Cell, Anaplastic - enzymology; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - pathology; Medical sciences; Mice; Mice, Nude; Neoplasia; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Receptor Protein-Tyrosine Kinases; Retroviridae - genetics; RNA Interference; RNA, Small Interfering - genetics; Transfection
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-05-2125

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 G1 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.