文章：

BET抑制作为原发性儿科b前体急性淋巴细胞白血病的单一或联合治疗方法

BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia

原文发布日期：2013-07-19

DOI: 10.1038/bcj.2013.24

类型: Original Article

开放获取: 是

英文摘要：

Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment.

摘要翻译： 

儿童B细胞前体型急性淋巴细胞白血病（ALL）是一种治愈率较高的疾病，然而部分患者的治疗耐药性以及现有疗法的长期毒性作用，使得开发更具靶向性的治疗方法成为必要。我们研究了JQ1（一种针对转录调节因子溴结构域和超末端结构域（BET）蛋白家族的高选择性抑制剂）在儿童ALL中的细胞毒性作用。研究发现，JQ1对一组原发性ALL细胞株表现出强效的体外细胞毒性反应，这种反应不依赖于其预后特征，而是与高MYC表达相关，并伴随多种促生存通路的转录下调。与早期研究一致，JQ1可诱导细胞周期停滞。本研究进一步表明，BET抑制还能降低c-Myc蛋白稳定性，并抑制ALL细胞中DNA复制叉的进展。与c-Myc耗竭和促生存通路下调的结果一致，JQ1使原发性ALL样本对经典ALL治疗药物地塞米松的敏感性增强。最后，我们证实JQ1在ALL异种移植模型中能单药或联合地塞米松共同抑制白血病生长。我们得出结论：靶向BET蛋白应被视为治疗儿童ALL的新策略，特别是对标准治疗反应不佳的病例。

原文链接：

BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia