The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways.
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.
Lim
Megan S
MS
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Carlson
Mary L
ML
Crockett
David K
DK
Fillmore
G Chris
GC
Abbott
David R
DR
Elenitoba-Johnson
Olaotan F
OF
Tripp
Sheryl R
SR
Rassidakis
George Z
GZ
Medeiros
L Jeffrey
LJ
Szankasi
Philippe
P
Elenitoba-Johnson
Kojo S J
KS
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
D020543:Proteome; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases