BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma

Purpose: BRD9 is a defining component of the noncanonical (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting SWI/SNF complex, which regulates gene expression by control-chimera; BRD9 degrader) approaches downregulated ribosome ling chromatin dynamics. Although recent studies have found an biogenesis genes, decreased the expression of the master regulator oncogenic role for BRD9 in multiple cancer types including MYC, and disrupted the protein-synthesis maintenance machinery, multiple myeloma, its clinical significance and oncogenic mechthereby inhibiting multiple myeloma cell growth in vitro and in vivo anism have not yet been elucidated. Here, we sought to identify in preclinical models. Importantly, we identified that the expression the clinical and biological impact of BRD9 in multiple myeloma, of ribosome biogenesis genes was associated with the disease which may contribute to the development of novel therapeutic progression and prognosis of patients with multiple myeloma. Our strategies. results suggest that BRD9 promotes gene expression by predomExperimental Design: We performed integrated analyses of inantly occupying the promoter regions of ribosome biogenesis BRD9 in vitro and in vivo using multiple myeloma cell lines and genes and cooperating with BRD4 to enhance the transcriptional primary multiple myeloma cells in established preclinical models, function of MYC. which identified the molecular functions of BRD9 contributing to Conclusions: Our study identifies and validates BRD9 as a novel multiple myeloma cell survival. therapeutic target in preclinical models of multiple myeloma, which Results: We found that high BRD9 expression was a poor provides the framework for the clinical evaluation of BRD9 degraprognostic factor in multiple myeloma. Depleting BRD9 by genetic ders to improve patient outcome.