The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of multiple myeloma. Although pomalidomide offers considerable clinical benefits to patients with lenalidomide-resistant multiple myeloma, the molecular mechanisms underlying its superior efficacy remain unclear. Here we show that ARID2, a component of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4^CRBN. BRD7, another subunit of PBAF, is critical for pomalidomide-induced ARID2 degradation. ARID2 is involved in transcriptional regulation of pomalidomide target genes including MYC. Pomalidomide is more effective than lenalidomide in degrading ARID2 and is capable of inhibiting MYC expression and proliferation in lenalidomide-resistant cell lines. Notably, ARID2 expression is associated with a poor prognosis and is higher in chemoresistant minimal residual disease (MRD) populations, and in patients with relapsed/refractory multiple myeloma. These findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma.

免疫调节药物（IMiD）沙利度胺及其衍生物来那度胺和泊马度胺是用于治疗多发性骨髓瘤的治疗剂。尽管泊马度胺为来那度胺耐药的多发性骨髓瘤患者提供了相当大的临床益处，但其优越疗效的分子机制仍不清楚。在这里，我们表明 ARID2 是多溴相关 BAF (PBAF) 染色质重塑复合物的一个组成部分，是一种 pomalidomide 诱导的 CRL4 CRBN 新底^物。BRD7 是 PBAF 的另一个亚基，对 pomalidomide 诱导的 ARID2 降解至关重要。ARID2 参与 pomalidomide 靶基因的转录调控，包括MYC。Pomalidomide 在降解 ARID2 方面比来那度胺更有效，并且能够抑制MYC在来那度胺耐药细胞系中的表达和增殖。值得注意的是，ARID2 表达与不良预后相关，并且在耐药性微小残留病 (MRD) 人群和复发/难治性多发性骨髓瘤患者中更高。这些发现表明，ARID2 是克服多发性骨髓瘤患者来那度胺耐药性的一个有希望的靶点。