Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response
Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response
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DOI：
10.1111/j.1365-2141.2011.08689.x
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发表时间：
2011-08-01
影响因子：
6.5
通讯作者：
Chopra, Rajesh
中科院分区：
文献类型：
--
作者：
Lopez-Girona, Antonia;Heintel, Daniel;Chopra, Rajesh
在多发性骨髓瘤（MM）中常见的转录因子干扰素调节因子-4（IRF 4）的过表达与不良预后相关。IRF 4高表达患者的总体生存率显著低于IRF 4低表达患者。来那度胺是一种IMiD（R）免疫调节化合物，在MM中具有杀肿瘤和免疫调节活性。这项研究表明，来那度胺在药物暴露8小时内下调了MM细胞系和骨髓样本中的IRF 4水平。这与MYC水平降低以及初始G1细胞周期停滞、细胞增殖降低和治疗第5天细胞死亡相关。在8个MM细胞系中，高IRF 4水平与来那度胺敏感性增加相关。在154例MM患者中研究了这一观察结果的临床意义。在回顾性分析中，在IRF 4高表达的MM患者中，来那度胺治疗导致总生存期显著长于其他治疗。这些数据证实了IRF 4在MM发病机制中的核心作用;表明这是来那度胺发挥其抗肿瘤作用的重要机制;并可能提供预测来那度胺反应的机制生物标志物。
Overexpression of the transcription factor interferon regulatory factor-4 (IRF4), which is common in multiple myeloma (MM), is associated with poor prognosis. Patients with higher IRF4 expression have significantly poorer overall survival than those with low IRF4 expression. Lenalidomide is an IMiD (R) immunomodulatory compound that has both tumouricidal and immunomodulatory activity in MM. This study showed that lenalidomide downregulated IRF4 levels in MM cell lines and bone marrow samples within 8 h of drug exposure. This was associated with a decrease in MYC levels, as well as an initial G1 cell cycle arrest, decreased cell proliferation, and cell death by day 5 of treatment. In eight MM cell lines, high IRF4 levels correlated with increased lenalidomide sensitivity. The clinical significance of this observation was investigated in 154 patients with MM. Among MM patients with high levels of IRF4 expression, treatment with lenalidomide led to a significantly longer overall survival than other therapies in a retrospective analysis. These data confirm the central role of IRF4 in MM pathogenesis; indicate that this is an important mechanism by which lenalidomide exerts its antitumour effects; and may provide a mechanistic biomarker to predict response to lenalidomide.