MYC deregulation occurs in the majority of multiple myeloma (MM) cases and is associated with progression and worse prognosis. Enhanced MYC expression occurs in about 70% of MM patients, but it is known to be driven by translocation or amplification events in only ~40% of myelomas. Here, we used CRISPR interference (CRISPRi) to uncover an epigenetic mechanism of MYC regulation whereby increased accessibility of a plasma cell-type specific enhancer leads to increased MYC expression. This native enhancer activity was not associated with enhancer hijacking events but led to specific binding of c-MAF, IRF4, and SPIB transcription factors that activated MYC expression in the absence of known genetic aberrations. In addition, focal amplification was another mechanism of activation of this enhancer in approximately 3.4% of MM patients. Together, these findings define an epigenetic mechanism of MYC deregulation in MM beyond known translocations or amplifications and point to the importance of non-coding regulatory elements and their associated transcription factor networks as drivers of MM progression.

中文翻译：

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选择性增强子功能增强可解除多发性骨髓瘤中 MYC 表达的调节


MYC 失调发生在大多数多发性骨髓瘤 (MM) 病例中，并且与进展和较差的预后相关。约 70% 的 MM 患者中出现 MYC 表达增强，但已知仅约 40% 的骨髓瘤是由易位或扩增事件驱动的。在这里，我们使用 CRISPR 干扰 (CRISPRi) 揭示了 MYC 调节的表观遗传机制，即浆细胞类型特异性增强子的可及性增加导致 MYC 表达增加。这种天然增强子活性与增强子劫持事件无关，但导致 c-MAF、IRF4 和 SPIB 转录因子的特异性结合，从而在不存在已知遗传畸变的情况下激活 MYC 表达。此外，在约 3.4% 的 MM 患者中，局部放大是该增强子激活的另一种机制。总之，这些发现定义了 MM 中 MYC 失调的表观遗传机制，超出了已知的易位或扩增范围，并指出了非编码调控元件及其相关转录因子网络作为 MM 进展驱动因素的重要性。