Proteomics-Based Approach Reveals the Involvement of SERPINB9 in Recurrent and Relapsed Multiple Myeloma
Proteomics-Based Approach Reveals the Involvement of SERPINB9 in Recurrent and Relapsed Multiple Myeloma
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基于蛋白质组学的方法揭示了 SERPINB9 在复发性多发性骨髓瘤中的作用
DOI：
10.1021/acs.jproteome.1c00007
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发表时间：
2021-03-02
影响因子：
4.4
通讯作者：
Liu, Aichun
中科院分区：
文献类型：
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作者：
Chen, Yao;Quan, Lina;Liu, Aichun
多发性骨髓瘤(MM)是一种常见的血液系统恶性肿瘤，其复发和复发机制知之甚少。值得注意的是，对Bortezomib的耐药性会导致复发，这使得MM的治疗具有重大的挑战性。为了阐明耐药机制，我们采用定量蛋白质组学方法来鉴定与耐药复发多发性骨髓瘤(RRMM)相关的差异表达的蛋白质候选。用串联质谱仪(TMT-MS)对5例初诊多发性骨髓瘤(NDMM)患者和5例耐药RRMM患者的骨髓抽吸物进行了比较。通过基因本体论、京都基因和基因组路径百科全书和等级聚类分析确定差异表达蛋白的亚细胞定位和功能分类。使用11个NDMM和8个RRMM患者的组织样本进行平行反应监测(PRM)分析，然后与10个MM患者和10个健康对照的NCBI基因表达总表(GEO)数据集(登录号：GSE80608)进行比较。用TMT-MS鉴定了RRMM中的34个差异表达蛋白，其中包括蛋白酶抑制因子9(SERPINB9)。随后对识别的候选蛋白进行的功能丰富分析表明，它们参与了RRMM中的细胞代谢、细胞凋亡、程序性细胞死亡、淋巴细胞介导的免疫和防御反应途径的调节。通过PRM分析和Western blotting以及与NCBI GEO数据集的比较，确定了最佳候选蛋白质SERPINB9。我们阐明了耐药的RRMM的蛋白质组图谱，并确定SERPINB9是一个有希望的新的治疗靶点。我们的研究结果为进一步研究RRMM的作用机制提供了资源。
Multiple myeloma (MM) is a common hematological malignancy with poorly understood recurrence and relapse mechanisms. Notably, bortezomib resistance leading to relapse makes MM treatment significantly challenging. To clarify the drug resistance mechanism, we employed a quantitative proteomics approach to identify differentially expressed protein candidates implicated in bortezomib-resistant recurrent and relapsed MM (RRMM). Bone marrow aspirates from five patients newly diagnosed with MM (NDMM) were compared with those from five patients diagnosed with bortezomib-resistant RRMM using tandem mass tag-mass spectrometry (TMT-MS). Subcellular localization and functional classification of the differentially expressed proteins were determined by gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and hierarchical clustering analyses. The top candidates identified were validated with parallel reaction monitoring (PRM) analysis using tissue samples from 11 NDMM and 8 RRMM patients, followed by comparison with the NCBI Gene Expression Omnibus (GEO) dataset of 10 MM patients and 10 healthy controls (accession no.: GSE80608). Thirty-four differentially expressed proteins in RRMM, including proteinase inhibitor 9 (SERPINB9), were identified by TMT-MS. Subsequent functional enrichment analyses of the identified protein candidates indicated their involvement in regulating cellular metabolism, apoptosis, programmed cell death, lymphocyte-mediated immunity, and defense response pathways in RRMM. The top protein candidate SERPINB9 was confirmed by PRM analysis and western blotting as well as by comparison with an NCBI GEO dataset. We elucidated the proteome landscape of bortezomib-resistant RRMM and identified SERPINB9 as a promising novel therapeutic target. Our results provide a resource for future studies on the mechanism of RRMM.