Immunomodulatory agents (IMiDs) are a major class of drugs for treating multiple myeloma (MM); however, acquired resistance to IMiDs remains a significant clinical challenge. While alterations in cereblon (CRBN) and its pathway are known to contribute to IMiD resistance, they account for only 20-30% of cases, and the underlying mechanisms in the majority of the resistance cases remain unclear. Here, we identified ADAR1 as a novel driver of lenalidomide resistance in MM. We showed that lenalidomide activates the MDA5-mediated dsRNA-sensing pathway in MM cells, leading to interferon (IFN)-mediated apoptosis, with ADAR1 as the key regulator. Mechanistically, ADAR1 loss increased lenalidomide sensitivity through endogenous dsRNA accumulation, which in turn triggered dsRNA-sensing pathways and enhanced IFN responses. Conversely, ADAR1 overexpression reduced lenalidomide sensitivity, attributed to increased RNA editing frequency, reduced dsRNA accumulation and suppression of the dsRNA-sensing pathways. In summary, we report the involvement of ADAR1-regulated dsRNA-sensing in modulating lenalidomide sensitivity in MM. These findings highlight a novel RNA-related mechanism underlying lenalidomide resistance and underscore the potential of targeting ADAR1 as a novel therapeutic strategy.

中文翻译：

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ADAR1 调节的细胞质 dsRNA 感应通路是多发性骨髓瘤来那度胺耐药的新机制。


免疫调节剂 （IMiD） 是治疗多发性骨髓瘤 （MM） 的一类主要药物;然而，对 IMiD 的获得性耐药仍然是一个重大的临床挑战。虽然已知 cereblon （CRBN） 及其通路的改变会导致 IMiD 耐药，但它们仅占病例的 20-30%，并且大多数耐药病例的潜在机制仍不清楚。在这里，我们确定 ADAR1 是 MM 中来那度胺耐药的新驱动因素。我们发现来那度胺激活 MM 细胞中 MDA5 介导的 dsRNA 感应通路，导致干扰素 （IFN） 介导的细胞凋亡，其中 ADAR1 是关键调节因子。从机制上讲，ADAR1 缺失通过内源性 dsRNA 积累增加了来那度胺的敏感性，这反过来又触发了 dsRNA 感应通路并增强了 IFN 反应。相反，ADAR1 过表达降低了来那度胺的敏感性，这归因于 RNA 编辑频率增加、dsRNA 积累减少和 dsRNA 感应通路的抑制。总之，我们报道了 ADAR1 调节的 dsRNA 传感在调节 MM 中来那度胺敏感性的参与。这些发现强调了来那度胺耐药性背后的一种新的 RNA 相关机制，并强调了靶向 ADAR1 作为一种新型治疗策略的潜力。