Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma.

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.

多发性骨髓瘤（MM）是一种与多种基因损伤相关的浆细胞肿瘤。尽管存在这种基因异质性，但多发性骨髓瘤具有一种特征性的恶性表型，其潜在的分子基础仍未得到充分阐明。在本研究中，我们使用多表观基因组学方法对多发性骨髓瘤的浆细胞进行了检测，并证明与正常B细胞相比，恶性浆细胞显示出调控元件的广泛激活，部分影响了协同调控的相邻基因。在这一过程上调的靶基因中，我们发现了NOTCH、NF -κB、mTOR信号通路和TP53信号通路的成员。其他激活的基因包括参与成骨细胞分化和氧化应激反应的基因集，所有这些都已被证明与多发性骨髓瘤的表型和临床行为相关。我们对控制硫氧还蛋白（TXN）表达的多发性骨髓瘤特异性活性远端增强子进行了功能鉴定，硫氧还蛋白是细胞氧化还原状态的主要调节因子，此外，我们还将PRDM5鉴定为多发性骨髓瘤的一个新的关键基因。总之，我们的数据表明，染色质异常激活是恶性浆细胞表型的一个统一特征。