Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Blood Cancer J. 2022 Jul 19;12(7):110. doi: 10.1038/s41408-022-00704-7.
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.
溴结构域蛋白 9（BRD9）是 SWI/SNF 染色质重塑复合物的必需组成部分，称为 ncBAF，已被确立为某些肉瘤和白血病的治疗靶点。在这里，我们使用新型小分子抑制剂和降解剂以及 RNA 干扰来评估 BRD9 在多种血液系统恶性肿瘤中的依赖性，包括急性髓系白血病（AML）、急性淋巴细胞白血病（ALL）和多发性骨髓瘤（MM）模型系统。BRD9 蛋白耗尽后，AML 细胞发生终末分化，而 ALL 和 MM 中则更明显的是细胞凋亡。急性白血病和 MM 细胞的 RNA-seq 分析显示，BRD9 降解影响的信号通路既有独特的也有共同的，共同的通路包括与炎症调节、细胞黏附、DNA 修复和细胞周期进展相关的通路。BRD9 的降解增强了几种针对 AML、ALL 和 MM 的化疗药物和靶向治疗药物的疗效。我们的研究结果支持进一步开发针对 BRD9 的治疗靶向，单独或与其他药物联合使用，作为治疗急性白血病和 MM 的一种新策略。
