Nature Medicine11, 623 - 629 (2005)
Published online: 15 May 2005; | doi:10.1038/nm1249
Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target
Roberto Chiarle1, 2, William J Simmons1, Honjying Cai1, Girish Dhall1, 3, Alberto Zamo4, Regina Raz1, James G Karras5, David E Levy1
& Giorgio Inghirami1, 2
1
Department of Pathology and NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, New York
10016, USA.
2
Center for Experimental Research and Medical Studies (CERMS) and Department of Biomedical Sciences and Human Oncology, University of Torino, Via Santena 7, Torino
10126, Italy.
3
Department of Pediatric Oncology, New York University School of Medicine, 550 First Avenue, New York, New York
10016, USA.
4
Department of Pathology, University of Verona, Strada Le Grazie 8, Borgo Roma, Verona, Italy.
5
ISIS Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California
92008, USA.
Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK−transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma.
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