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.

含溴结构域蛋白 9 (BRD9) 是称为 ncBAF 的 SWI/SNF 染色质重塑复合物的重要组成部分，已被确定为肉瘤和白血病子集的治疗靶点。在这里，我们使用新型小分子抑制剂和降解剂以及 RNA 干扰来评估在各种血液恶性肿瘤（包括急性髓性白血病 (AML)、急性淋巴细胞白血病 (ALL) 和多发性骨髓瘤 (MM) 模型）中对 BRD9 的依赖性系统。在 BRD9 蛋白耗尽后，AML 细胞经历终末分化，而凋亡在 ALL 和 MM 中更为突出。急性白血病和 MM 细胞的 RNA-seq 分析揭示了受 BRD9 降解影响的独特和常见的信号通路，常见的通路包括与炎症、细胞粘附、DNA 修复和细胞周期进程。BRD9 的降解增强了几种化疗药物和靶向治疗对 AML、ALL 和 MM 的作用。我们的研究结果支持进一步开发 BRD9 的治疗靶向，单独或与其他药物联合，作为急性白血病和 MM 的新策略。