文章：

BRD9降解剂作为急性白血病和多发性骨髓瘤的化学增敏剂

BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma

原文发布日期：2022-07-19

DOI: 10.1038/s41408-022-00704-7

类型: Article

开放获取: 是

英文摘要：

Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM.
 

摘要翻译： 

含有溴结构域的蛋白质9（BRD9）作为被称为ncBAF的SWI/SNF染色质重塑复合物的关键组分，已被确定为部分肉瘤和白血病的治疗靶点。本研究利用新型小分子抑制剂和降解剂以及RNA干扰技术，评估了在急性髓系白血病（AML）、急性淋巴细胞白血病（ALL）和多发性骨髓瘤（MM）等多种血液恶性肿瘤模型系统中对BRD9的依赖性。BRD9蛋白被耗竭后，AML细胞发生终末分化，而ALL和MM细胞则更显著地出现凋亡。通过对急性白血病和MM细胞的RNA测序分析，发现BRD9降解影响的信号通路既有独特性也存在共同性，共同通路包括炎症调节、细胞粘附、DNA修复及细胞周期进程相关通路。BRD9降解增强了多种化疗药物及靶向疗法对AML、ALL和MM的治疗效果。我们的研究结果支持进一步开发针对BRD9的单药或联合治疗方案，将其作为治疗急性白血病和MM的新型策略。

原文链接：

BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma