Translational Development Department, Celgene, San Diego, CA 92122, USA.
Br J Haematol. 2011 Aug;154(3):325-36. doi: 10.1111/j.1365-2141.2011.08689.x. Epub 2011 Jun 24.
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 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.
转录因子干扰素调节因子-4（IRF4）的过度表达在多发性骨髓瘤（MM）中很常见，与预后不良相关。IRF4 表达较高的患者总生存期明显短于 IRF4 表达较低的患者。来那度胺是一种 IMiD 免疫调节化合物，在 MM 中具有细胞毒性和免疫调节活性。这项研究表明，来那度胺在药物暴露 8 小时内即可下调 MM 细胞系和骨髓样本中的 IRF4 水平。这与 MYC 水平下降以及初始 G1 细胞周期停滞、细胞增殖减少和治疗第 5 天的细胞死亡有关。在 8 个 MM 细胞系中，IRF4 水平升高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 IRF4 高表达的 MM 患者中，回顾性分析表明，与其他疗法相比，来那度胺治疗可显著延长总生存期。这些数据证实了 IRF4 在 MM 发病机制中的核心作用；表明这是来那度胺发挥抗肿瘤作用的重要机制；并可能提供一种预测来那度胺反应的机制生物标志物。
