title: 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.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.forename: Mary L
authors.initials: ML
authors.lastname: Carlson
authors.forename: David K
authors.initials: DK
authors.lastname: Crockett
authors.forename: G Chris
authors.initials: GC
authors.lastname: Fillmore
authors.forename: David R
authors.initials: DR
authors.lastname: Abbott
authors.forename: Olaotan F
authors.initials: OF
authors.lastname: Elenitoba-Johnson
authors.forename: Sheryl R
authors.initials: SR
authors.lastname: Tripp
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Philippe
authors.initials: P
authors.lastname: Szankasi
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
mesh_terms: D000595:Amino Acid Sequence; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019169:Jurkat Cells; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000032:analysis* / Q000378:metabolism; D040901:Proteomics; D019893:Ribosomal Protein S6 Kinases / Q000737:chemistry / Q000378:metabolism; D046888:Tissue Array Analysis; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D020543:Proteome; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases