Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
Department of Pathology, University Regensburg, Regensburg, Germany.
Mol Cell Proteomics. 2019 May;18(5):936-953. doi: 10.1074/mcp.RA119.001390. Epub 2019 Feb 21.
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 of MM cells 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.
多发性骨髓瘤（MM）是一种不可治愈的浆细胞恶性肿瘤，主要局限于骨髓（BM）内。它由恶性前体阶段，意义未明的单克隆丙种球蛋白血症（MGUS）发展而来，通常通过中间阶段，冒烟型多发性骨髓瘤（SMM）发展而来。MM 进展的机制尚未完全了解，尤其是因为 MGUS 和 SMM 患者已经携带与 MM 细胞中发现的相似的初始突变。近年来，肿瘤微环境及其在疾病病理生理学中的作用受到了越来越多的重视。已经表明，MM 细胞对 BM 缺氧条件的适应对 MM 的进展有重要贡献，而与肿瘤细胞的遗传倾向无关。为了寻找缺氧诱导适应对原发性人 MM 细胞的影响，我们通过蛋白质组谱分析对从不同疾病阶段患者的 BM 中新鲜分离的 CD138 阳性浆细胞（包括 MGUS、SMM 和 MM）进行了分析，这导致了 6218 种蛋白质的鉴定。结果已通过 ProteomeXchange 标识符 PXD010600 完全公开。为了进行比较，还包括了先前从正常原代 B 细胞获得的数据。主成分分析显示了三个聚类，将 B 细胞以及 MM 细胞区分开来，对应于疾病较轻和较重的阶段。比较这三个聚类，表明在疾病进展过程中，MM 细胞中存在适应缺氧应激的途径发生改变。通过免疫组织化学染色确定了 MM 细胞逃避免疫的策略，以及参与 MM 发生和进展的转录因子，确定了蛋白质调节。细胞代谢适应的蛋白质调节网络变得明显。通过对 MM 细胞和 MM 相关成纤维细胞中选定代谢物的靶向分析，加强了结果。基于我们的数据，可能会出现针对多发性骨髓瘤疾病进展的治疗策略的新机会。
