Title of article :
Constitutive activation of Jak2 contributes to proliferation and resistance to apoptosis in NPM/ALK-transformed cells
Author/Authors :
Holger Ruchatz، نويسنده , , Addolorata Maria Luce Coluccia، نويسنده , , Paola Stano، نويسنده , , Edoardo Marchesi، نويسنده , , Carlo Gambacorti-Passerini، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2003
Pages :
7
From page :
309
To page :
315
Abstract :
Objectives The t(2;5) translocation results in a 80-kDa oncogenic fusion protein consisting of NPM and the kinase domain of the tyrosine kinase ALK and is present in over half the cases of anaplastic large cell lymphoma (ALCL). NPM/ALK exerts its transforming potential via activation of multiple signaling pathways promoting growth factor independence and protection from apoptosis. Jak/Stat signaling is aberrantly activated in several human hematopoietic malignancies. We investigated the role of Jak2 in the context of NPM/ALK-mediated oncogenesis. Materials and Methods Constitutive tyrosine phosphorylation of Jak2 was analyzed by Jak2 immunoprecipitation and subsequent anti-phosphotyrosine Western blotting. NPM/ALK-transformed cells were treated with the Jak2 inhibitor AG490 or transfected with wild-type or dominant-negative Jak2 expression constructs to measure 3[H]-thymidine incorporation. Apoptosis was assessed by flow cytometric analysis of annexin V–stained cells. The effect of Jak2 on Stat5-dependent transcriptional activity was measured by β-casein promoter-dependent luciferase expression. Results Jak2 was found to be constitutively tyrosine phosphorylated in ALCL cells and in NPM/ALK-transformed hematopoietic cells. Also, NPM/ALK was present in immunoprecipitates of Jak2. Inhibition of Jak2 led to a reduction of NPM/ALK-mediated proliferation and induced apoptosis. Stat5-dependent transcriptional activity was inhibited by transfection of NPM/ALK-transformed cells with a dominant-negative Jak2 expression construct or treatment with AG490. Conclusion Constitutive activation of Jak2 constitutes a pro-proliferative, anti-apoptotic signaling pathway in NPM/ALK-transformed hematopoietic cells.
Journal title :
Experimental Hematology
Serial Year :
2003
Journal title :
Experimental Hematology
Record number :
513832
Link To Document :
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