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    Integrated cellular and plasma proteomics of contrasting b-cell cancers reveals common, unique and systemic signatures.

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    Authors
    Johnston, H
    Carter, M
    Cox, K
    Dunscombe, M
    Manousopoulou, A
    Townsend, Paul A
    Garbis, S
    Cragg, M
    Affiliation
    Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, General Hospital, University of Southampton, Southampton
    Issue Date
    2017-03
    
    Metadata
    Show full item record
    Abstract
    Approximately 800,000 leukemia and lymphoma cases are diagnosed worldwide each year. Burkitt's lymphoma (BL) and chronic lymphocytic leukemia (CLL) are examples of contrasting B-cell cancers; BL is a highly aggressive lymphoid tumor, frequently affecting children, whereas CLL typically presents as an indolent, slow-progressing leukemia affecting the elderly. The B-cell-specific overexpression of the myc and TCL1 oncogenes in mice induce spontaneous malignancies modeling BL and CLL, respectively. Quantitative mass spectrometry proteomics and isobaric labeling were employed to examine the biology underpinning contrasting Eμ-myc and Eμ-TCL1 B-cell tumors. Additionally, the plasma proteome was evaluated using subproteome enrichment to interrogate biomarker emergence and the systemic effects of tumor burden. Over 10,000 proteins were identified (q<0.01) of which 8270 cellular and 2095 plasma proteins were quantitatively profiled. A common B-cell tumor signature of 695 overexpressed proteins highlighted ribosome biogenesis, cell-cycle promotion and chromosome segregation. Eμ-myc tumors overexpressed several methylating enzymes and underexpressed many cytoskeletal components. Eμ-TCL1 tumors specifically overexpressed ER stress response proteins and signaling components in addition to both subunits of the interleukin-5 (IL5) receptor. IL5 treatment promoted Eμ-TCL1 tumor proliferation, suggesting an amplification of IL5-induced AKT signaling by TCL1. Tumor plasma contained a substantial tumor lysis signature, most prominent in Eμ-myc plasma, whereas Eμ-TCL1 plasma contained signatures of immune-response, inflammation and microenvironment interactions, with putative biomarkers in early-stage cancer. These findings provide a detailed characterization of contrasting B-cell tumor models, identifying common and specific tumor mechanisms. Integrated plasma proteomics allowed the dissection of a systemic response and a tumor lysis signature present in early- and late-stage cancers, respectively. Overall, this study suggests common B-cell cancer signatures exist and illustrates the potential of the further evaluation of B-cell cancer subtypes by integrative proteomics.
    Citation
    Integrated cellular and plasma proteomics of contrasting b-cell cancers reveals common, unique and systemic signatures. 2017, 16 (3):386-406 Mol. Cell Proteomics
    Journal
    Molecular & Cellular Proteomics
    URI
    http://hdl.handle.net/10541/620345
    DOI
    10.1074/mcp.M116.063511
    PubMed ID
    28062796
    Type
    Article
    Language
    en
    ISSN
    1535-9484
    ae974a485f413a2113503eed53cd6c53
    10.1074/mcp.M116.063511
    Scopus Count
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    All Paterson Institute for Cancer Research

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