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Blood, 19 March 2009, Vol. 113, No. 12, pp. 2776-2790. Prepublished online as a Blood First Edition Paper on October 9, 2008; DOI 10.1182/blood-2008-06-161018. This Article Full Text Full Text (PDF) Supplemental Methods and Tables All Versions of this Article: blood-2008-06-161018v1 113/12/2776    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Boccalatte, F. E. Articles by Inghirami, G. Search for Related Content PubMed PubMed Citation Articles by Boccalatte, F. E. Articles by Inghirami, G. Related Collections Lymphoid Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL Francesco E. Boccalatte1,2,*, Claudia Voena1,2,*, Chiara Riganti1,3, Amalia Bosia1,3, Lucia D'Amico1,2, Ludovica Riera1,2, Mangeng Cheng4, Bruce Ruggeri4, Ole N. Jensen5, Valerie L. Goss6, Kimberly Lee6, Julie Nardone6, John Rush6, Roberto D. Polakiewicz6, Michael J. Comb6, Roberto Chiarle1,2, and Giorgio Inghirami1,2,7 1 Center for Experimental Research and Medical Studies (CERMS), 2 Department of Biomedical Sciences and Human Oncology, and 3 Department of Genetics, Biology, and Biochemistry, University of Torino, Torino, Italy; 4 Discovery Research, Cephalon, West Chester, PA; 5 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark; 6 Cell Signaling Technology, Danvers, MA; and 7 Department of Pathology and New York University Cancer Center, New York University School of Medicine, New York Anaplastic large cell lymphoma represents a subset of neoplasms caused by translocations that juxtapose the anaplastic lymphoma kinase (ALK) to dimerization partners. The constitutive activation of ALK fusion proteins leads to cellular transformation through a complex signaling network. To elucidate the ALK pathways sustaining lymphomagenesis and tumor maintenance, we analyzed the tyrosine-kinase protein profiles of ALK-positive cell lines using 2 complementary proteomic-based approaches, taking advantage of a specific ALK RNA interference (RNAi) or cell-permeable inhibitors. A well-defined set of ALK-associated tyrosine phosphopeptides, including metabolic enzymes, kinases, ribosomal and cytoskeletal proteins, was identified. Validation studies confirmed that vasodilator-stimulated phosphoprotein and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) associated with nucleophosmin (NPM)–ALK, and their phosphorylation required ALK activity. ATIC phosphorylation was documented in cell lines and primary tumors carrying ALK proteins and other tyrosine kinases, including TPR-Met and wild type c-Met. Functional analyses revealed that ALK-mediated ATIC phosphorylation enhanced its enzymatic activity, dampening the methotrexate-mediated transformylase activity inhibition. These findings demonstrate that proteomic approaches in well-controlled experimental settings allow the definition of informative proteomic profiles and the discovery of novel ALK downstream players that contribute to the maintenance of the neoplastic phenotype. Prediction of tumor responses to methotrexate may justify specific molecular-based chemotherapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Unraveling ALK signaling through phosphoproteomics Megan S. Lim Blood 2009 113: 2615-2616. [Full Text] [PDF] This article has been cited by other articles: Y. P. Mosse, A. Wood, and J. M. Maris Inhibition of ALK Signaling for Cancer Therapy Clin. Cancer Res., September 15, 2009; 15(18): 5609 - 5614. [Abstract] [Full Text] [PDF] B. Falini and M. P. Martelli Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy Haematologica, July 1, 2009; 94(7): 897 - 900. [Full Text] [PDF] M. S. Lim Unraveling ALK signaling through phosphoproteomics Blood, March 19, 2009; 113(12): 2615 - 2616. [Full Text] [PDF]

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