title: Integrated Cellular and Plasma Proteomics of Contrasting B-cell Cancers Reveals Common, Unique and Systemic Signatures.
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 themycandTCL1oncogenes 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-mycand Eμ-TCL1B-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-myctumors overexpressed several methylating enzymes and underexpressed many cytoskeletal components. Eμ-TCL1tumors specifically overexpressed ER stress response proteins and signaling components in addition to both subunits of the interleukin-5 (IL5) receptor. IL5 treatment promoted Eμ-TCL1tumor proliferation, suggesting an amplification of IL5-induced AKT signaling by TCL1. Tumor plasma contained a substantial tumor lysis signature, most prominent in Eμ-mycplasma, whereas Eμ-TCL1plasma 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.
authors.affiliation: From the ‡Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, General Hospital, University of Southampton, Southampton SO16 6YD, UK.|§Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK.
authors.forename: Harvey E
authors.identifier: 0000-0001-7032-0227
authors.initials: HE
authors.lastname: Johnston
authors.affiliation: From the ‡Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, General Hospital, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Carter
authors.affiliation: From the ‡Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, General Hospital, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Cox
authors.affiliation: From the ‡Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, General Hospital, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Dunscombe
authors.affiliation: §Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK.|¶Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Antigoni
authors.initials: A
authors.lastname: Manousopoulou
authors.affiliation: ‖Molecular and Clinical Cancer Sciences, Paterson Building, Manchester Cancer Research Centre, Manchester Academic Health Science Centre, University of Manchester, Manchester, M20 4BX.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Townsend
authors.affiliation: §Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK.|¶Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Spiros D
authors.identifier: 0000-0002-1050-0805
authors.initials: SD
authors.lastname: Garbis
authors.affiliation: From the ‡Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, General Hospital, University of Southampton, Southampton SO16 6YD, UK; msc@soton.ac.uk.
authors.forename: Mark S
authors.identifier: 0000-0003-2077-089X
authors.initials: MS
authors.lastname: Cragg
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000097:blood / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D040901:Proteomics / Q000379:methods*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C489428:Myc protein, mouse; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C490393:Tcl1 protein, mouse