BCL2-associated athanogene-1 (BAG1) is a multi-functional protein that is found deregulated in several solid cancers and in paediatric acute myeloid leukaemia. The investigation of BAG1 isoforms expression and intracellular localization in B-cell acute lymphoblastic leukaemia (B-ALL) patient-derived specimens revealed that BAG1 levels decrease during disease remission, compared to diagnosis, but drastically increase at relapse. In particular, at diagnosis both BAG1-L and BAG1-M isoforms are mainly nuclear, while during remission the localization pattern changes, having BAG1-M almost exclusively in the cytosol indicating its potential cytoprotective role in B-ALL. In addition, knockdown of BAG1/BAG3 induces cell apoptosis and G1-phase cell cycle arrest and, more intriguingly, shapes cell response to chemotherapy. BAG1-depleted cells show an increased sensitivity to the common chemotherapeutic agents, dexamethasone or daunorubicin, and to the BCL2 inhibitor ABT-737. Moreover, the BAG1 inhibitor Thio-2 induces a cytotoxic effect on RS4;11 cells both in vitro and in a zebrafish xenograft model and strongly synergizes with pan-BCL inhibitors. Collectively, these data sustain BAG1 deregulation as a critical event in assuring survival advantage to B-ALL cells.

中文翻译：

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BAG1下调增加急性淋巴细胞白血病细胞的化学敏感性

BCL2 相关的 athanogene-1 (BAG1) 是一种多功能蛋白，在几种实体癌和小儿急性髓性白血病中发现失调。对 B 细胞急性淋巴细胞白血病 (B-ALL) 患者衍生标本中 BAG1 同种型表达和细胞内定位的研究表明，与诊断相比，BAG1 水平在疾病缓解期间降低，但在复发时急剧增加。特别是，在诊断时，BAG1-L 和 BAG1-M 同种型主要是细胞核，而在缓解期间，定位模式发生变化，BAG1-M 几乎只存在于细胞质中，表明其在 B-ALL 中具有潜在的细胞保护作用。此外，BAG1/BAG3 的敲低诱导细胞凋亡和 G1 期细胞周期停滞，更有趣的是，塑造细胞对化疗的反应。BAG1 耗尽的细胞对常见的化疗药物地塞米松或柔红霉素以及对 BCL2 抑制剂 ABT-737 的敏感性增加。此外，BAG1 抑制剂 Thio-2 在体外和斑马鱼异种移植模型中均对 RS4;11 细胞产生细胞毒性作用，并与泛 BCL 抑制剂具有强烈的协同作用。总的来说，这些数据支持 BAG1 失调作为确保 B-ALL 细胞存活优势的关键事件。