Integrated Cellular and Plasma Proteomics of Contrasting B-cell Cancers Reveals Common, Unique and Systemic Signatures
Integrated Cellular and Plasma Proteomics of Contrasting B-cell Cancers Reveals Common, Unique and Systemic Signatures
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DOI：
10.1074/mcp.m116.063511
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发表时间：
2017-03-01
影响因子：
7
通讯作者：
Cragg, Mark S.
中科院分区：
文献类型：
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作者：
Johnston, Harvey E.;Carter, Matthew J.;Cragg, Mark S.
全世界每年大约诊断出80万例白血病和淋巴瘤病例。Burkitt淋巴瘤(BL)和慢性淋巴细胞性白血病(CLL)是对比B细胞癌的例子；BL是一种高度侵袭性的淋巴肿瘤，经常影响儿童，而CLL通常表现为一种影响老年人的惰性、进展缓慢的白血病。B细胞特异性的myc和TCL1癌基因在小鼠体内的过度表达分别诱导了自发性恶性肿瘤的发生。采用定量质谱学、蛋白质组学和等压标记等方法，研究对比E-Mu-myc和E-Mu-TCL1 B细胞肿瘤的生物学基础。此外，血浆蛋白质组通过亚蛋白质组浓缩来评估生物标记物的出现和肿瘤负荷的系统效应。鉴定了10,000多个蛋白质(Q<；0.01)，其中8270个细胞蛋白质和2095个血浆蛋白质被定量分析。695种过表达蛋白的一个共同的B细胞肿瘤特征突出了核糖体的生物发生、细胞周期促进和染色体分离。E-Mu-myc肿瘤高表达几种甲基化酶，低表达许多细胞骨架成分。E-MU-TCL1肿瘤除了白介素5(IL5)受体的两个亚单位外，还特异性地过度表达ER应激反应蛋白和信号成分。IL5处理可促进E-MU-TCL1肿瘤细胞的增殖，提示TCL1可放大IL5诱导的AKT信号转导。肿瘤血浆包含大量的肿瘤溶解信号，在E Mu-myc血浆中最为突出，而E Mu-TCL1血浆包含免疫反应、炎症和微环境相互作用的信号，与早期癌症的假定生物标志物有关。这些发现提供了对比B细胞肿瘤模型的详细特征，确定了共同和特定的肿瘤机制。整合的血浆蛋白质组学可以分别分析早期和晚期癌症中存在的全身反应和肿瘤溶解特征。总体而言，这项研究表明存在共同的B细胞癌特征，并说明了通过整合蛋白质组学进一步评估B细胞癌亚型的潜力。
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 E mu-myc and E mu-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. E mu-myc tumors overexpressed several methylating enzymes and underexpressed many cytoskeletal components. E mu-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 E mu-TCL1 tumor proliferation, suggesting an amplification of IL5-induced AKT signaling by TCL1. Tumor plasma contained a substantial tumor lysis signature, most prominent in E mu-myc plasma, whereas E mu-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.