Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, N-7491, Trondheim, Norway.
Clinic of Laboratory Medicine, St. Olavs hospital, N-7491, Trondheim, Norway.
J Transl Med. 2024 Jun 7;22(1):548. doi: 10.1186/s12967-024-05345-x.
Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can guide initial treatment decisions and help determine suitable replacement or adjuvant therapies when relapse ensues due to acquired drug resistance.
To define specific proteins and pathways involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), we have applied super-SILAC quantitative proteomic analysis to CD138 + plasma cells from 9 individuals with MGUS and 37 with MM.
Unsupervised hierarchical clustering defined three groups: MGUS, MM, and MM with an MGUS-like proteome profile (ML) that may represent a group that has recently transformed to MM. Statistical analysis identified 866 differentially expressed proteins between MM and MGUS, and 189 between MM and ML, 177 of which were common between MGUS and ML. Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated.
Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. Our analyses identified a range of novel biomarkers with potential prognostic and therapeutic value, which will undergo further evaluation to determine their clinical significance.
尽管在治疗策略方面取得了重大进展，但多发性骨髓瘤仍然无法治愈。此外，缺乏可靠的生物标志物来指导初始治疗决策，并在因获得性药物耐药而复发时帮助确定合适的替代或辅助治疗。
为了确定与意义未明的单克隆丙种球蛋白血症（MGUS）进展为多发性骨髓瘤（MM）相关的特定蛋白质和途径，我们应用超 SILAC 定量蛋白质组学分析方法对 9 例 MGUS 和 37 例 MM 的 CD138+浆细胞进行了分析。
无监督层次聚类将三个组定义为：MGUS、MM 和 MM 与 MGUS 样蛋白组谱（ML），这可能代表最近转化为 MM 的一组。统计分析在 MM 和 MGUS 之间鉴定出 866 个差异表达蛋白，在 MM 和 ML 之间鉴定出 189 个，其中 177 个在 MGUS 和 ML 之间共同存在。从 MGUS 进展为 MM 伴随着 EIF2 信号、DNA 修复和参与翻译质量控制的蛋白质上调，而整合素和肌动蛋白细胞骨架信号和细胞表面标志物下调。
与 MGUS 中的前恶性浆细胞相比，恶性 MM 细胞显然已经动员了几种途径，这些途径共同有助于确保翻译保真度并避免蛋白毒性应激，特别是在 ER 中。免疫球蛋白和表面抗原的总体低表达促成了这一点，并且可能另外介导了逃避免疫系统的识别。我们的分析确定了一系列具有潜在预后和治疗价值的新型生物标志物，它们将进一步评估以确定其临床意义。
