IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma (ATAC-Seq human 8)

Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease. Overall design: ATAC sequencing to determine open chromatin profiles in NCH929 and SKMM1 multiple myeloma cells treated with control (DMSO) versus 1000 nM AU15330 for 4 hours.

多发性骨髓瘤（Multiple myeloma, MM）是一类不可治愈的浆细胞恶性肿瘤，其通过利用维持正常浆细胞生物学功能的转录调控网络，驱动恶性增殖与存活。转录因子干扰素调节因子4（IRF4）是决定浆细胞身份的核心调控因子，多发性骨髓瘤细胞的存活依赖于IRF4的表达。为发掘多发性骨髓瘤中独特的分子易感靶点，本研究采用整合功能基因组筛选、空间蛋白质组学与全基因组染色质图谱分析的多组学研究策略。研究发现，作为SWI/SNF染色质重塑复合物成员的ARID1A，不仅是IRF4表达所必需的分子，还在染色质层面与IRF4蛋白存在功能关联。在活化的小鼠B细胞中条件性敲除Arid1a，会通过破坏IRF4依赖的转录调控网络，阻断后续浆细胞分化进程，由此确定ARID1A是浆细胞的全新易感靶点。通过靶向ARID1A依赖的SWI/SNF活性（采用SMARCA2/4抑制策略），可快速降低IRF4靶基因的表达水平，并抑制MYC驱动的全基因组致癌性基因表达扩增，从而对多发性骨髓瘤细胞产生强烈的杀伤毒性。值得注意的是，在侵袭性多发性骨髓瘤患者中，SWI/SNF依赖的基因呈现上调表达；且SMARCA2/4抑制剂对免疫调节剂（immunomodulatory drug, IMiD）耐药的多发性骨髓瘤细胞仍保有抗肿瘤活性。为充分发挥这类药物的治疗潜力，本研究通过联合药物筛选，发现SMARCA2/4抑制剂与MEK抑制剂之间存在极强的协同杀伤效应。因此，靶向SWI/SNF活性可强效抑制IRF4-MYC正向反馈环路，为治疗这一不可治愈的恶性肿瘤提供了可行的临床转化策略。实验整体设计：对分别经对照处理（二甲基亚砜（DMSO））与1000 nM AU15330处理4小时的NCH929和SKMM1多发性骨髓瘤细胞进行ATAC测序（ATAC sequencing），以解析其开放染色质图谱。