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首页> 外文期刊>Molecular & cellular proteomics: MCP >Metabolic, Anti-apoptotic and Immune Evasion Strategies of Primary Human Myeloma Cells Indicate Adaptations to Hypoxia
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Metabolic, Anti-apoptotic and Immune Evasion Strategies of Primary Human Myeloma Cells Indicate Adaptations to Hypoxia

机译：原发性人骨髓瘤细胞的代谢，抗凋亡和免疫逃避策略表明对缺氧的适应性

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Multiple Myeloma (MM) is an incurable plasma cell malignancy primarily localized within the bone marrow (BM). It develops from a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage, smoldering MM (SMM). The mechanisms of MM progression have not yet been fully understood, all the more because patients with MGUS and SMM already carry similar initial mutations as found in MM cells. Over the last years, increased importance has been attributed to the tumor microenvironment and its role in the pathophysiology of the disease. Adaptations of MM cells to hypoxic conditions in the BM have been shown to contribute significantly to MM progression, independently from the genetic predispositions of the tumor cells. Searching for consequences of hypoxia-induced adaptations in primary human MM cells, CD138-positive plasma cells freshly isolated from BM of patients with different disease stages, comprising MGUS, SMM, and MM, were analyzed by proteome profiling, which resulted in the identification of 6218 proteins. Results have been made fully accessible via ProteomeXchange with identifier PXD010600. Data previously obtained from normal primary B cells were included for comparative purposes. A principle component analysis revealed three clusters, differentiating B cells as well as MM cells corresponding to less and more advanced disease stages. Comparing these three clusters pointed to the alteration of pathways indicating adaptations to hypoxic stress in MM cells on disease progression. Protein regulations indicating immune evasion strategies ofMMcells were determined, supported by immunohistochemical staining, as well as transcription factors involved in MM development and progression. Protein regulatory networks related to metabolic adaptations of the cells became apparent. Results were strengthened by targeted analyses of a selected panel of metabolites in MM cells and MM-associated fibroblasts. Based on our data, new opportunities may arise for developing therapeutic strategies targeting myeloma disease progression. Molecular & Cellular Proteomics 18: 936-953, 2019. DOI:10.1074/mcp.RA119.001390.
机译：多发性骨髓瘤（mm）是主要局部局部在骨髓（BM）内的可治区血浆细胞恶性肿瘤。它从未动脉的阶段开发出不确定的显着意义（MGU）的单克隆血管病，通常通过中间阶段，闷烧MM（SMM）。 MM进展的机制尚未得到完全理解，越多越好，因为MGU和SMM的患者已经携带了MM细胞中发现的类似初始突变。在过去几年中，增加了重要性归因于肿瘤微环境及其在疾病病理生理学中的作用。已显示MM细胞对BM中缺氧条件的适应，从肿瘤细胞的遗传易感性独立于MM进展显着贡献至MM进展。通过蛋白质组分析分析了从不同疾病阶段的不同疾病阶段的患者新分离的缺氧诱导的适应的后果，CD138阳性血浆细胞，蛋白质组分析分析了蛋白质组分析，导致鉴定6218蛋白。通过具有标识符PXD010600的Proteomexchange可以完全访问的结果。以比较目的包括预先从正常的初级B细胞获得的数据。一个原理分量分析显示了三种簇，区分B细胞以及对应于较少和更晚期疾病阶段的MM细胞。比较这三种簇指向途径改变，表明在疾病进展上患MM细胞中对缺氧应激的改变。确定了蛋白质法规，其测定了免疫组化染色的MMCells的免疫逃避策略，以及参与MM发育和进展的转录因子。与细胞的代谢适应有关的蛋白质调节网络变得明显。通过在MM细胞和MM相关成纤维细胞中靶向分析的靶向分析来加强结果。基于我们的数据，可能出现新的机会，以发展患有骨髓瘤病进展的治疗策略。分子和细胞蛋白质组学18：936-953,2017。DOI：10.1074 / MCP.RA119.001390。

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