Total Proteome Analysis Identifies Migration Defects as a Major Pathogenetic Factor in Immunoglobulin Heavy Chain Variable Region (IGHV)-unmutated Chronic Lymphocytic Leukemia

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Eagle, Gina ORCID: 0000-0002-7381-2355, Zhuang, Jack ORCID: 0000-0003-3245-0789, Jenkins, Roz, Till, Kathy ORCID: 0000-0002-3172-5771, Jithesh, Puthen, Lin, Ke, Johnson, Gillian, Oates, Melanie, Park, Kevin ORCID: 0000-0001-8384-824X, Kitteringham, Neil et al (show 1 more authors) and Pettitt, Andrew (2015) Total Proteome Analysis Identifies Migration Defects as a Major Pathogenetic Factor in Immunoglobulin Heavy Chain Variable Region (IGHV)-unmutated Chronic Lymphocytic Leukemia. Molecular and Cellular Proteomics, 14 (4). pp. 933-945.

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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.

Item Type:	Article
Uncontrolled Keywords:	Cell Line, Tumor, Humans, Lymphatic Diseases, Immunoglobulin Variable Region, Neoplasm Proteins, Proteome, Blotting, Western, Reproducibility of Results, Isotope Labeling, Proteomics, Computational Biology, Cell Movement, Chemotaxis, Mutation, Aged, Female, Immunoglobulin Heavy Chains, Male, Mass Spectrometry, Leukemia, Lymphocytic, Chronic, B-Cell, Chemokine CCL21
Subjects:	?? RB ?? ?? RC0254 ??
Depositing User:	Symplectic Admin
Date Deposited:	24 Sep 2015 10:04
Last Modified:	19 Jan 2023 07:38
DOI:	10.1074/mcp.M114.044479
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2010008

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• Total Proteome Analysis Identifies Migration Defects as a Major Pathogenetic Factor in Immunoglobulin Heavy Chain Variable Region (IGHV)-unmutated Chronic Lymphocytic Leukemia. (deposited 24 Sep 2015 10:04) [Currently Displayed]