The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways.

Abstract

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.

• Authors: 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, Kojo S J Elenitoba-Johnson
• Journal: Blood (Blood) Vol. 114 Issue 8 Pg. 1585-95 (Aug 20 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19531656 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proteome
• p80(NPM-ALK) protein
• Protein-Tyrosine Kinases
• Ribosomal Protein S6 Kinases

Topics

• Amino Acid Sequence
• Gene Expression Regulation, Neoplastic
• Humans
• Jurkat Cells
• Lymphoma, Large-Cell, Anaplastic (metabolism)
• Metabolic Networks and Pathways (genetics, physiology)
• Models, Biological
• Molecular Sequence Data
• Protein-Tyrosine Kinases (genetics, metabolism)
• Proteome (analysis, metabolism)
• Proteomics
• Ribosomal Protein S6 Kinases (chemistry, metabolism)
• Tissue Array Analysis
• Transfection
• Tumor Cells, Cultured