title: Total proteome analysis identifies migration defects as a major pathogenetic factor in immunoglobulin heavy chain variable region (IGHV)-unmutated chronic lymphocytic leukemia.
abstract: The mutational status of the immunoglobulin heavy chain variable region defines two clinically distinct forms of chronic lymphocytic leukemia (CLL) known as mutated (M-CLL) and unmutated (UM-CLL). To elucidate the molecular mechanisms underlying the adverse clinical outcome associated with UM-CLL, total proteomes from nine UM-CLL and nine M-CLL samples were analyzed by isobaric tags for relative and absolute quantification (iTRAQ)-based mass spectrometry. Based on the expression of 3521 identified proteins, principal component analysis separated CLL samples into two groups corresponding to immunoglobulin heavy chain variable region mutational status. Computational analysis showed that 43 cell migration/adhesion pathways were significantly enriched by 39 differentially expressed proteins, 35 of which were expressed at significantly lower levels in UM-CLL samples. Furthermore, UM-CLL cells underexpressed proteins associated with cytoskeletal remodeling and overexpressed proteins associated with transcriptional and translational activity. Taken together, our findings indicate that UM-CLL cells are less migratory and more adhesive than M-CLL cells, resulting in their retention in lymph nodes, where they are exposed to proliferative stimuli. In keeping with this hypothesis, analysis of an extended cohort of 120 CLL patients revealed a strong and specific association between UM-CLL and lymphadenopathy. Our study illustrates the potential of total proteome analysis to elucidate pathogenetic mechanisms in cancer.
authors: From the ‡Department of Molecular and Clinical Cancer Medicine.
authors: Gina L
authors: GL
authors: Eagle
authors: From the ‡Department of Molecular and Clinical Cancer Medicine, j.zhuang@liverpool.ac.uk.
authors: Jianguo
authors: J
authors: Zhuang
authors: §MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GA, UK;
authors: Rosalind E
authors: RE
authors: Jenkins
authors: From the ‡Department of Molecular and Clinical Cancer Medicine.
authors: Kathleen J
authors: KJ
authors: Till
authors: From the ‡Department of Molecular and Clinical Cancer Medicine.
authors: Puthen V
authors: PV
authors: Jithesh
authors: ¶Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool L7 8XP, UK.
authors: Ke
authors: K
authors: Lin
authors: ¶Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool L7 8XP, UK.
authors: Gillian G
authors: GG
authors: Johnson
authors: From the ‡Department of Molecular and Clinical Cancer Medicine.
authors: Melanie
authors: M
authors: Oates
authors: §MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GA, UK;
authors: Kevin
authors: K
authors: Park
authors: §MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GA, UK;
authors: Neil R
authors: NR
authors: Kitteringham
authors: From the ‡Department of Molecular and Clinical Cancer Medicine, ¶Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool L7 8XP, UK a.r.pettitt@liverpool.ac.uk.
authors: Andrew R
authors: AR
authors: Pettitt
mesh_terms: D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054421:Chemokine CCL21 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D019295:Computational Biology; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007553:Isotope Labeling; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008206:Lymphatic Diseases / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D015203:Reproducibility of Results
chemical_list: D054421:Chemokine CCL21; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D009363:Neoplasm Proteins; D020543:Proteome
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