尽管治疗方法最近取得了进展，多发性骨髓瘤（MM）仍然是一种无法治愈的恶性肿瘤。表观遗传因素导致多发性骨髓瘤的发生、进展、复发和克隆异质性，但我们对多发性骨髓瘤发生的表观遗传机制的了解还远未完成。 SAGA 复合物充当转录中的共激活子并催化乙酰化和去泛素化。对癌症依赖性图项目中数据集的分析表明，许多 SAGA 组件在 MM 中是选择性依赖性的。为了定义 SAGA 特有的功能，我们重点关注 ADA2B，它是赖氨酸乙酰转移酶 (KAT) 模块中唯一在 SAGA 中专门发挥作用的亚基。整合 RNA 测序 (RNA-seq)、转座酶可及染色质测序分析 (ATAC-seq)，以及使用核酸酶分析 (CUT) 进行目标切割和释放

Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity in MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator in transcription and catalyzes acetylation and deubiquitylation. Analyses of data sets in the Cancer Dependency Map Project revealed that many SAGA components are selective dependencies in MM. To define SAGA-specific functions, we focused on ADA2B, the only subunit in the lysine acetyltransferase (KAT) module that specifically functions in SAGA. Integration of RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and cleavage under targets and release using nuclease assay (CUT&RUN) results identified pathways directly regulated by ADA2B including MTORC1 signaling and oncogenic programs driven by MYC, E2F, and MM-specific MAF. We discovered that ADA2B is recruited to MAF and MYC gene targets, and that MAF shares a majority of its targets with MYC in MM cells. Furthermore, we found that the SANT domain of ADA2B is required for interaction with both GCN5 and PCAF acetyltransferases, incorporation into SAGA, and ADA2B protein stability. Our findings uncover previously unknown SAGA KAT module-dependent mechanisms controlling MM cell growth, revealing a vulnerability that might be exploited for future development of MM therapy.© 2024 Chen et al.; Published by Cold Spring Harbor Laboratory Press.