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Blood, 20 August 2009, Vol. 114, No. 8, pp. 1585-1595. Prepublished online as a Blood First Edition Paper on June 16, 2009; DOI 10.1182/blood-2009-02-204735. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2009-02-204735v1 114/8/1585    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 CrossRef Google Scholar Articles by Lim, M. S. Articles by Elenitoba-Johnson, K. S. J. PubMed PubMed Citation Articles by Lim, M. S. Articles by Elenitoba-Johnson, K. S. J. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways Megan S. Lim1, Mary L. Carlson2, David K. Crockett3, G. Chris Fillmore2, David R. Abbott2, Olaotan F. Elenitoba-Johnson3, Sheryl R. Tripp3, George Z. Rassidakis4, L. Jeffrey Medeiros4, Philippe Szankasi3, and Kojo S. J. Elenitoba-Johnson1 1 Department of Pathology, University of Michigan, Ann Arbor; 2 University of Utah Health Sciences Center, Salt Lake City; 3 ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT; and 4 Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p32;q35) is a key oncogenic event in the pathogenesis of most anaplastic large cell lymphomas (ALCLs). The proteomic network alterations produced by this aberration remain largely uncharacterized. Using a mass spectrometry (MS)–driven approach to identify changes in protein expression caused by the NPM/ALK fusion, we identified diverse NPM/ALK-induced changes affecting cell proliferation, ribosome synthesis, survival, apoptosis evasion, angiogenesis, and cytoarchitectural organization. MS-based findings were confirmed using Western blotting and/or immunostaining of NPM/ALK-transfected cells and ALK-deregulated lymphomas. A subset of the proteins distinguished NPM/ALK-positive ALCLs from NPM/ALK-negative ALCLs and Hodgkin lymphoma. The multiple NPM/ALK-deregulated pathways identified by MS analysis also predicted novel biologic effects of NPM/ALK expression. In this regard, we showed loss of cell adhesion as a consequence of NPM/ALK expression in a kinase-dependent manner, and sensitivity of NPM/ALK-positive ALCLs to inhibition of the RAS, p42/44ERK, and FRAP/mTOR signaling pathways. These findings reveal that the NPM/ALK alteration affects diverse cellular pathways, and provide novel insights into NPM/ALK-positive ALCL pathobiology. Our studies carry important implications for the use of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers, and pathogenetically relevant therapeutic targets. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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