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Abstract：
Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy.
摘要：
多发性骨髓瘤是由分泌免疫球蛋白的浆细胞引起的血液恶性肿瘤。尚不清楚调节元件的染色质重新布线如何导致骨髓瘤的肿瘤发生和治疗抵抗。在这里，我们通过整合骨髓瘤细胞系中的H3K27acChIP-seq和HiChIP来生成骨髓瘤相关超增强子的高分辨率接触图，患者来源的骨髓瘤细胞和正常浆细胞。我们全面的转录组和表型分析优先考虑在骨髓瘤中具有生物学和临床意义的候选基因。我们显示骨髓瘤细胞经常获得SE，其转录激活癌基因PPP1R15B，编码全磷酸酶复合物的调节亚基，该亚基使翻译起始因子eIF2α去磷酸化。PPP1R15B的表观遗传沉默或敲低激活促凋亡eIF2α-ATF4-CHOP通路，同时抑制蛋白质合成和免疫球蛋白的产生。使用Raphin1对PPP1R15B的药理学抑制增强了硼替佐米的抗骨髓瘤作用。我们的研究表明，骨髓瘤细胞易受PPP1R15B依赖性蛋白质稳态的干扰，突出了一个有前途的治疗策略。
