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

Abstract

Approximately 800,000 leukaemia and lymphoma cases are diagnosed worldwide each year. Burkitt's lymphoma (BL) and chronic lymphocytic leukaemia (CLL), are examples of contrasting B-cell cancers; BL is a highly aggressive lymphoid tumour, frequently affecting children, whilst CLL typically presents as an indolent, slow-progressing leukaemia affecting the elderly. The B-cell-specific over-expression of the myc and tcl1 oncogenes in mice induce spontaneous malignancies modelling BL and CLL, respectively. Quantitative mass spectrometry proteomics and isobaric labelling were employed to examine the biology underpinning contrasting E?-myc and E?-TCL1 B-cell tumours. Additionally, the plasma proteome was evaluated using sub-proteome enrichment to interrogate biomarker emergence and the systemic effects of tumour 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 tumour signature of 695 over-expressed proteins highlighted ribosome biogenesis, cell-cycle promotion and chromosome segregation. E?-myc tumours over-expressed several methylating enzymes and under-expressed many cytoskeletal components. E?-TCL1 tumours specifically over-expressed ER stress response proteins and signalling components in addition to both subunits of the interleukin-5 (IL5) receptor. IL5 treatment promoted E?-TCL1 tumour proliferation, suggesting an amplification of IL5-induced AKT signalling by TCL1. Tumour plasma contained a substantial tumour lysis signature, most prominent in E?-myc plasma, whilst E?-TCL1 plasma contained signatures of immune-response, inflammation and microenvironment interactions, with putative biomarkers in early-stage cancer. These findings provide a detailed characterisation of contrasting B-cell tumour models, identifying common and specific tumour mechanisms. Integrated plasma proteomics allowed the dissection of a systemic response and a tumour 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.

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Identifiers

ORCID for Spiros Garbis: orcid.org/0000-0002-1050-0805

ORCID for Mark Cragg: orcid.org/0000-0003-2077-089X

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