title: Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma.
abstract: Accumulating evidence indicates that expression of anaplastic lymphoma kinase (ALK), typically due to t(2;5) translocation, defines a distinct type of T/null-cell lymphoma (TCL). The resulting nucleophosmin (NPM) /ALK chimeric kinase is constitutively active and oncogenic. Downstream effector molecules triggered by NPM/ALK remain, however, largely unidentified. Here we report that NPM/ALK induces continuous activation of STAT3. STAT3 displayed tyrosine phosphorylation and DNA binding in all (four of four) ALK+ TCL cell lines tested. The activation of STAT3 was selective because none of the other known STATs was consistently tyrosine phosphorylated in these cell lines. In addition, malignant cells in tissue sections from all (10 of 10) ALK+ TCL patients expressed tyrosine-phosphorylated STAT3. Transfection of BaF3 cells with NPM/ALK resulted in tyrosine phosphorylation of STAT3. Furthermore, STAT3 was constitutively associated with NPM/ALK in the ALK+ TCL cell lines. Additional studies into the mechanisms of STAT3 activation revealed that the ALK+ TCL cells expressed a positive regulator of STAT3 activation, protein phosphatase 2A (PP2A), which was constitutively associated with STAT3. Treatment with the PP2A inhibitor calyculin A abrogated tyrosine phosphorylation of STAT3. Finally, ALK+ T cells failed to express a negative regulator of activated STAT3, protein inhibitor of activated STAT3. These data indicate that NPM/ALK activates STAT3 and that PP2A and lack of protein inhibitor of activated STAT3 may be important in maintaining STAT3 in the activated state in the ALK+ TCL cells. These results also suggest that activated STAT3, which is known to display oncogenic properties, as well as its regulatory molecules may represent attractive targets for novel therapies in ALK+ TCL.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Puthryaveett N
authors.initials: PN
authors.lastname: Raghunath
authors.forename: Liquan
authors.initials: L
authors.lastname: Xue
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Majewski
authors.forename: David F
authors.initials: DF
authors.lastname: Carpentieri
authors.forename: Niels
authors.initials: N
authors.lastname: Odum
authors.forename: Stephan
authors.initials: S
authors.lastname: Morris
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D016399:Lymphoma, T-Cell / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D054648:Protein Phosphatase 2; D011505:Protein-Tyrosine Kinases / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012334:RNA, Neoplasm; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D019000:Phosphotyrosine; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2