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Blood, 15 September 2005, Vol. 106, No. 6, pp. 2175-2182.
Prepublished online as a Blood First Edition Paper on May 31, 2005; DOI 10.1182/blood-2005-01-0316.
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Submitted January 25, 2005
Accepted May 22, 2005
Activation of  -diacylglycerol kinase is critical for the mitogenic properties of anaplastic lymphoma kinase
Roberta Bacchiocchi, Gianluca Baldanzi, Damiano Carbonari, Catia Capomagi, Emanuela Colombo, Wim J van Blitterswijk, Andrea Graziani, and Francesca Fazioli*
Laboratory of Cellular and Molecular Biology, Institute of Clinical Medicine and Applied Biotechnologies, Polytechnic University of the Marche Region, Ancona, Italy
Laboratory of Biochemistry, Department of Medical Sciences, University "Amedeo Avogadro" of Piemonte Orientale, Novara, Italy; Centro Ricerche "E. Menni", Ospedale Poliambulanza Brescia, Brescia, Italy
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Laboratory of Biochemistry, Department of Medical Sciences, University "Amedeo Avogadro" of Piemonte Orientale, Novara, Italy
* Corresponding author; email: fazioli{at}univpm.it.
Oncogenic rearrangements of the tyrosine kinase receptor Anaplastic Lymphoma Kinase (ALK), most commonly represented by the nucleophosmin/ALK fusion protein (NPM/ALK), are involved in the pathogenesis of Anaplastic Large Cell Lymphomas (ALCLs). In an effort to identify new intracellular transducers operative in ALK-positive malignancies, we have investigated the potential involvement of diacylglycerol kinase (DGK). Here we show that  DGK is constitutively activated in the NPM/ALK positive ALCL-derived cell line Karpas 299 and in NPM/ALK-infected 32D hematopoietic cells. These results were further validated in fibroblastic NIH-3T3 cells expressing a previously described chimeric Epidermal Growth Factor Receptor (EGFR)/ALK molecule that allows dissection of ALK enzymatic function under condition of controlled ligand-induced activation. In this cell system we also show that ALK-mediated DGK activation is dependent on p60src tyrosine kinase, with which DGK forms a complex. The specific inhibition of DGK, obtained by cell treatment with R59949, significantly reduced cellular growth in all cell lines. This result was further confirmed in Karpas 299 following specific down-regulation of DGK by RNA interference. Overall our data indicate that DGK activation is involved in the control of ALK-mediated mitogenic properties.
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