文章：

双磷脂酰肌醇-3激酶和mTOR阻断在细胞周期蛋白D2阳性多发性骨髓瘤中对细胞周期进程的抑制

Inhibition of cell cycle progression by dual phosphatidylinositol-3-kinase and mTOR blockade in cyclin D2 positive multiple myeloma bearing IgH translocations

原文发布日期：2012-01-13

DOI: 10.1038/bcj.2011.44

类型: Original Article

开放获取: 是

英文摘要：

Multiple myeloma (MM) is a clinically and genetically heterogenous cancer where tumour cells have dysregulated expression of a D-type cyclin, often in association with a recurrent IgH translocation. Patients whose tumour cells express cyclin D2, with the translocation t(4;14) or t(14;16), generally have more proliferative disease and inferior outcomes. The phosphatidylinositol-3-kinase (PI3K) pathway is a major regulator of D-type cyclin expression and cell cycle entry. We evaluated the effect of PI3K pathway blockade on cell cycle behaviour in MM cells, investigating differences between cyclin D2- and cyclin D1-expressing tumours. MM cell lines and primary bone marrow CD138+ MM cells were exposed to the pan-PI3K/mTOR inhibitor, PI-103, and assessed for cell cycle profiles, [3H]-thymidine uptake and cell cycle proteins. We report, in both cell lines and primary MM cells, that PI-103 induced cell cycle arrest with downregulation of cyclin D2 and CDK4/6 in MM cells expressing cyclin D2 via t(4;14) or t(14;16) translocations. Cells expressing cyclin D1 via t(11;14) were insensitive to PI-103, despite exhibiting inhibition of downstream signalling targets. In primary MM cells, PI-103 enhanced the anti-proliferative effects of anti-MM agents. Treatment paradigms including blockade of the PI3K/mTOR pathway should be targeted at patients with IgH translocations associated with cyclin D2 overexpression.

摘要翻译： 

多发性骨髓瘤（MM）是一种临床和遗传异质性肿瘤，其瘤细胞常出现D型细胞周期蛋白表达失调，并多伴有复发性IgH易位。瘤细胞表达细胞周期蛋白D2且存在t(4;14)或t(14;16)易位的患者通常疾病增殖性更强，预后更差。磷脂酰肌醇-3-激酶（PI3K）通路是D型细胞周期蛋白表达和细胞周期进入的主要调控因子。我们评估了阻断PI3K通路对MM细胞周期行为的影响，并比较细胞周期蛋白D2与D1表达型肿瘤的差异。MM细胞系和原发骨髓CD138+ MM细胞经泛PI3K/mTOR抑制剂PI-103处理后，检测其细胞周期分布、[3H]-胸苷摄取及细胞周期蛋白表达。结果显示，在细胞系和原发MM细胞中，PI-103均可通过t(4;14)或t(14;16)易位诱导细胞周期蛋白D2表达型MM细胞发生周期阻滞，并下调cyclin D2及CDK4/6。而经t(11;14)表达cyclin D1的细胞对PI-103不敏感，尽管其下游信号靶点仍被抑制。在原发MM细胞中，PI-103可增强抗MM药物的抗增殖效果。因此，包含PI3K/mTOR通路阻断的治疗方案应针对存在cyclin D2过表达相关IgH易位的患者。

原文链接：

Inhibition of cell cycle progression by dual phosphatidylinositol-3-kinase and mTOR blockade in cyclin D2 positive multiple myeloma bearing IgH translocations