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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.
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Submitted June 3, 2008
Accepted August 9, 2008
The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL
Francesco E. Boccalatte, Claudia Voena, Chiara Riganti, Amalia Bosia, Lucia D'Amico, Ludovica Riera, Mangeng Cheng, Bruce Ruggeri, Ole N Jensen, Valerie L Goss, Kimberly Lee, Julie Nardone, John Rush, Roberto D. Polakiewicz, Michael J Comb, Roberto Chiarle, and Giorgio Inghirami*
Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy
Department of Biomedical Sciences and Human Oncology, University of Torino, Torino, Italy
Department of Genetics, Biology, and Biochemistry, University of Torino, Torino, Italy
Discovery Research, Cephalon Inc., West Chester, PA, United States
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
Cell Signaling Technology, Inc., Danvers, MA, United States
Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, NY, United States
* Corresponding author; email: giorgio.inghirami{at}unito.it.
Anaplastic large cell lymphoma (ALCL) represent a subset of neoplasms often caused by translocations that juxtapose the anaplastic lymphoma kinase (ALK) to a dimerization partner. The constitutive activation of ALK fusion proteins leads to cellular transformation through a complex signaling network.
To further elucidate the ALK pathways sustaining lymphomagenesis and tumor maintenance, we analyzed the tyrosine-kinase protein profiles of ALK-positive cell lines using two 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 phospho-peptides, including metabolic enzymes, kinases, ribosomal and cytoskeletal proteins was identified. Validation studies confirmed that VASP and ATIC associated with NPM-ALK and their phosphorylation required ALK activity. ATIC phosphorylation was also 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, dampering the methotrexate-mediated transformylase activity inhibition. These findings demonstrate that alternative proteomic approaches in well-controlled experimental settings allow the definition of highly-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 the design of specific molecular-based chemotherapy.
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