Purpose: Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are cornerstone therapies in Multiple Myeloma (MM), yet patients inevitably become refractory. IMiDs exert cytotoxicity through inducing Cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of CRBN or IKZF1/3 has not been well-explored. Here, we investigated the roles of IRF4 and MYC in this context. Experimental Design: Using bone marrow aspirates from patients with IMiD naïve or refractory MM, we examined IKZF1/3 protein levels and IRF4/MYC gene expression following ex vivo pomalidomide treatment via flow cytometry and qPCR. We also assessed ex vivo sensitivity to the MYC inhibitor, MYCi975, using flow cytometry. Results: We discovered that while pomalidomide frequently led to IKZF1/3 degradation in MM cells, MYC gene expression was unaffected by pomalidomide in most IMiD refractory samples. We subsequently demonstrated that MYCi975 exerted strong anti-MM effects in both IMiD naïve and refractory samples. Unexpectedly, we identified CD8+ T cells from patients with MM as crucial effectors of MYCi975-induced cytotoxicity in primary MM samples, and we discovered MYCi975 enhanced the cytotoxic functions of memory CD8+ T cells. We lastly observed synergy between MYCi975 and pomalidomide in IMiD refractory samples, suggesting restoring MYC downregulation can re-sensitize refractory MM to IMiDs. Conclusion: Our study supports the concept that MYC represents an Achille’s heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs.

中文翻译：

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MYC 抑制增强 CD8+ T 细胞对抗多发性骨髓瘤并克服免疫调节耐药性

目的：免疫调节药物（IMiD），如来那度胺和泊马度胺，是多发性骨髓瘤（MM）的基础疗法，但患者不可避免地会变得难治。 IMiD 通过诱导 IKZF1 和 IKZF3 的 Cereblon 依赖性蛋白酶体降解来发挥细胞毒性，从而导致致癌转录因子 IRF4 和 MYC 的下调。迄今为止，独立于 CRBN 或 IKZF1/3 的临床 IMiD 耐药性尚未得到充分探索。在这里，我们研究了 IRF4 和 MYC 在此背景下的作用。实验设计：使用IMiD初治或难治性MM患者的骨髓抽吸物，我们通过流式细胞术和qPCR检查了离体泊马度胺治疗后的IKZF1/3蛋白水平和IRF4/MYC基因表达。我们还使用流式细胞术评估了对 MYC 抑制剂 MYCi975 的离体敏感性。结果：我们发现，虽然泊马度胺经常导致 MM 细胞中的 IKZF1/3 降解，但在大多数 IMiD 难治性样本中，MYC 基因表达不受泊马度胺影响。我们随后证明 MYCi975 在 IMiD 初始样品和难治性样品中都发挥了强大的抗 MM 作用。出乎意料的是，我们发现来自 MM 患者的 CD8+ T 细胞是原发性 MM 样本中 MYCi975 诱导的细胞毒性的关键效应器，并且我们发现 MYCi975 增强了记忆 CD8+ T 细胞的细胞毒性功能。我们最后在 IMiD 难治性样本中观察到 MYCi975 和泊马度胺之间的协同作用，表明恢复 MYC 下调可以使难治性 MM 对 IMiD 重新敏感。结论：我们的研究支持这样的观点，即 MYC 代表了不同疾病状态的 MM 的致命弱点，并且 MYCi975 可能是 MM 患者的一种有前景的治疗方法，特别是与 IMiD 联合使用。