Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells
Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells
复制标题
DOI：
10.3324/haematol.2009.014464
复制
发表时间：
2010-05-01
期刊：
影响因子：
--
通讯作者：
Kroeger, Nicolaus
中科院分区：
文献类型：
--
作者：
Atanackovic, Djordje;Hildebrandt, York;Kroeger, Nicolaus
多发性骨髓瘤是一种危及生命的疾病，尽管引入了干细胞移植和新型药物，如沙利度胺、来那度胺和硼替佐米，但大多数患者会复发并发展为化疗耐药疾病。因此，骨髓瘤需要替代的治疗模式，而cancer-睾丸抗原如MAGE-C1/CT7和MAGE-A3被认为是一类特别适合靶向免疫治疗的肿瘤特异性蛋白。令人惊讶的是，癌睾丸基因在骨髓瘤中的生物学作用仍然知之甚少。设计与方法采用基于RNA干扰的骨髓瘤细胞系基因沉默模型，首次研究了骨髓瘤中最常表达的两种癌睾丸抗原MAGE-C1/CT7和MAGE-A3的功能。功能分析用于确定基因特异性沉默导致的增殖、细胞粘附、化学敏感性、集落形成和凋亡的变化。结果所研究的基因不参与调节细胞增殖和粘附；然而，它们在促进骨髓瘤细胞的存活中起着重要作用。因此，MAGE-C1/CT7和MAGE-A3的敲低导致恶性浆细胞凋亡的诱导，重要的是，这两个基因对于克隆性骨髓瘤前体的存活也是必不可少的。最后，癌睾丸基因的沉默进一步改善了骨髓瘤细胞对常规疗法的反应。结论睾丸癌抗原如MAGE-C1/CT7和MAGE-A3通过降低自发性和化疗诱导的细胞凋亡率，在促进骨髓瘤细胞和克隆前体细胞的存活中发挥重要作用，因此可能是新型骨髓瘤特异性治疗的有吸引力的靶点。
BackgroundMultiple myeloma is a life-threatening disease and despite the introduction of stem cell transplantation and novel agents such as thalidomide, lenalidomide, and bortezomib most patients will relapse and develop chemoresistant disease. Therefore, alternative therapeutic modes for myeloma are needed and cancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 have been suggested to represent a class of tumor-specific proteins particularly suited for targeted immunotherapies. Surprisingly, the biological role of cancer-testis genes in myeloma remains poorly understood.Design and MethodsWe performed the first investigation of the function of two cancer-testis antigens most commonly expressed in myeloma, MAGE-C1/CT7 and MAGE-A3, using an RNA interference-based gene silencing model in myeloma cell lines. Functional assays were used to determine changes in proliferation, cell adhesion, chemosensitivity, colony formation, and apoptosis resulting from gene-specific silencing.ResultsWe show that the investigated genes are not involved in regulating cell proliferation or adhesion; however, they play an important role in promoting the survival of myeloma cells. Accordingly, knock-down of MAGE-C1/CT7 and MAGE-A3 led to the induction of apoptosis in the malignant plasma cells and, importantly, both genes were also essential for the survival of clonogenic myeloma precursors. Finally, silencing of cancer-testis genes further improved the response of myeloma cells to conventional therapies.ConclusionsCancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 play an important role in promoting the survival of myeloma cells and clonogenic precursors by reducing the rate of spontaneous and chemotherapy-induced apoptosis and might, therefore, represent attractive targets for novel myeloma-specific therapies.