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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.
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Submitted February 12, 2009
Accepted April 22, 2009
The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways
Megan S. Lim*, Mary L. Carlson, David K. Crockett, G. Chris Fillmore, David R. Abbott, Olaotan F. Elenitoba-Johnson, Sheryl R. Tripp, George Z. Rassidakis, L. Jeffrey Medeiros, Philippe Szankasi, and Kojo S.J. Elenitoba-Johnson
Department of Pathology, University of Michigan, Ann Arbor, MI, United States
University of Utah Health Sciences Center, Salt Lake City, UT, United States
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States
Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: meganlim{at}umich.edu.
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 (ALCL). 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 utilization of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers and pathogenetically-relevant therapeutic targets.
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