Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas.
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.
Piva
Roberto
R
Department of Pathology, Center for Experimental Research and Medical Studies, University of Turin, Italy.
Chiarle
Roberto
R
Manazza
Andrea D
AD
Taulli
Riccardo
R
Simmons
William
W
Ambrogio
Chiara
C
D'Escamard
Valentina
V
Pellegrino
Elisa
E
Ponzetto
Carola
C
Palestro
Giorgio
G
Inghirami
Giorgio
G
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D000090243:Nucleophosmin; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D034741:RNA, Small Interfering; D000090243:Nucleophosmin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases