基于基因表达预测骨髓瘤细胞对组蛋白去乙酰化酶抑制剂的敏感性。

BACKGROUND

Multiple myeloma (MM) is still a fatal plasma cell cancer. Novel compounds are currently clinically tested as a single agent in relapsing patients, but in best cases with partial response of a fraction of patients, emphasising the need to design tools predicting drug efficacy. Histone deacetylase inhibitors (HDACi) are anticancer agents targeting epigenetic regulation of gene expression and are in clinical development in MM.

METHODS

To create a score predicting HDACi efficacy, five MM cell lines were treated with trichostatin A (TSA) and gene expression profiles were determined.

RESULTS

The expression of 95 genes was found to be upregulated by TSA, using paired supervised analysis with Significance Analysis of Microarrays software. Thirty-seven of these 95 genes had prognostic value for overall survival in a cohort of 206 newly diagnosed MM patients and their prognostic information was summed up in a histone acetylation score (HA Score); patients with the highest HA Score had the shorter overall survival. It is worth noting that MM cell lines or patients' primary MM cells with a high HA Score had a significant higher sensitivity to TSA, valproic acid, panobinostat or vorinostat.

CONCLUSION

In conclusion, the HA Score allows identification of MM patients with poor survival, who could benefit from HDACi treatment.

背景

多发性骨髓瘤（MM）仍然是一种致命的浆细胞癌。目前，新型化合物作为单一药物在复发患者中进行临床试验，但在最佳情况下，只有一部分患者有部分缓解，这强调了需要设计预测药物疗效的工具。组蛋白去乙酰化酶抑制剂（HDACi）是一种针对基因表达表观遗传调控的抗癌药物，正在 MM 中进行临床开发。

方法

为了创建预测 HDACi 疗效的评分，用曲古抑菌素 A（TSA）处理五种 MM 细胞系，并确定基因表达谱。

结果

使用 Significance Analysis of Microarrays 软件进行配对监督分析，发现 95 个基因的表达被 TSA 上调。这 95 个基因中有 37 个在 206 例新诊断 MM 患者的队列中对总生存期具有预后价值，其预后信息汇总为组蛋白乙酰化评分（HA 评分）；HA 评分最高的患者总生存期较短。值得注意的是，具有高 HA 评分的 MM 细胞系或患者的原发性 MM 细胞对 TSA、丙戊酸、panobinostat 或 vorinostat 的敏感性显著提高。