Integrated cellular and plasma proteomics of contrasting b-cell cancers reveals common, unique and systemic signatures.
AffiliationAntibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, General Hospital, University of Southampton, Southampton
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AbstractApproximately 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.
CitationIntegrated cellular and plasma proteomics of contrasting b-cell cancers reveals common, unique and systemic signatures. 2017, 16 (3):386-406 Mol. Cell Proteomics
JournalMolecular & Cellular Proteomics
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- Issue date: 2014 Jan 14
- Eμ-TCL1xMyc: A Novel Mouse Model for Concurrent CLL and B-Cell Lymphoma.
- Authors: Lucas F, Rogers KA, Harrington BK, Pan A, Yu L, Breitbach J, Bundschuh R, Goettl VM, Hing ZA, Kanga P, Mantel R, Sampath D, Smith LL, Wasmuth R, White DK, Yan P, Byrd JC, Lapalombella R, Woyach JA
- Issue date: 2019 Oct 15
- Effect of rapamycin on mouse chronic lymphocytic leukemia and the development of nonhematopoietic malignancies in Emu-TCL1 transgenic mice.
- Authors: Zanesi N, Aqeilan R, Drusco A, Kaou M, Sevignani C, Costinean S, Bortesi L, La Rocca G, Koldovsky P, Volinia S, Mancini R, Calin G, Scott CP, Pekarsky Y, Croce CM
- Issue date: 2006 Jan 15
- Expression of A-myb, but not c-myb and B-myb, is restricted to Burkitt's lymphoma, sIg+ B-acute lymphoblastic leukemia, and a subset of chronic lymphocytic leukemias.
- Authors: Golay J, Luppi M, Songia S, Palvarini C, Lombardi L, Aiello A, Delia D, Lam K, Crawford DH, Biondi A, Barbui T, Rambaldi A, Introna M
- Issue date: 1996 Mar 1
- The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma.
- Authors: Hunter JE, Butterworth JA, Zhao B, Sellier H, Campbell KJ, Thomas HD, Bacon CM, Cockell SJ, Gewurz BE, Perkins ND
- Issue date: 2016 Jun 30