Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target.
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
Chiarle
Roberto
R
Department of Pathology and NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Simmons
William J
WJ
Cai
Honjying
H
Dhall
Girish
G
Zamo
Alberto
A
Raz
Regina
R
Karras
James G
JG
Levy
David E
DE
Inghirami
Giorgio
G
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000503:physiopathology*; D016399:Lymphoma, T-Cell / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000503:physiopathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D020794:Receptor Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*
D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases