美国国立卫生研究院Ryan M. Young小组发现，IRF4需要ARID1A在多发性骨髓瘤中建立浆细胞特性。该研究于2024年6月20日在线发表于国际一流学术期刊《癌细胞》。

研究人员采用多组学方法发现IRF4的弱点，将功能基因组学筛选、空间蛋白质组学和全局染色质图谱整合在一起。SWI/SNF染色质重塑复合物的成员ARID1A是IRF4表达所需的，并在功能上与染色质上的IRF4蛋白结合。在活化的小鼠B细胞中删除Arid1a会破坏IRF4依赖性转录网络并阻止浆细胞分化。靶向SWI/SNF活性会导致IRF4靶基因表达的快速丧失，并抑制MYC对致癌基因表达的全面扩增，从而对多发性骨髓瘤（MM）细胞产生深远的毒性。

值得注意的是，具有侵袭性疾病的MM患者具有SWI/SNF活性特征，SMARCA2/4抑制剂对免疫调节药物（IMiD）抗性MM细胞仍然有效。此外，SWI/SNF和MEK抑制剂的组合对MM细胞具有协同毒性，为复发/难治性疾病的治疗提供了一种前景广阔的策略。

据介绍，MM是一种无法治愈的浆细胞恶性肿瘤，它利用了由IRF4驱动的转录网络。

附：英文原文

Title: IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma

Author: Arnold Bolomsky, Michele Ceribelli, Sebastian Scheich, Kristina Rinaldi, Da Wei Huang, Papiya Chakraborty, Lisette Pham, George W. Wright, Tony Hsiao, Vivian Morris, Jaewoo Choi, James D. Phelan, Ronald J. Holewinski, Thorkell Andresson, Jan Wisniewski, Deanna Riley, Stefania Pittaluga, Elizabeth Hill, Craig J. Thomas, Jagan Muppidi, Ryan M. Young

Issue&Volume: 2024-06-20

Abstract: Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptionalnetworks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities,integrating functional genomics screening, spatial proteomics, and global chromatinmapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is requiredfor IRF4 expression and functionally associates with IRF4 protein on chromatin. DeletingArid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks andblocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid lossof IRF4-target gene expression and quenches global amplification of oncogenic geneexpression by MYC, resulting in profound toxicity to MM cells. Notably, MM patientswith aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitorsremain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinationsof SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providinga promising strategy for relapsed/refractory disease.

DOI: 10.1016/j.ccell.2024.05.026

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00217-4