文章：

多发性骨髓瘤患者NCOR2低表达通过上调MYC驱动多药耐药

Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation

原文发布日期：2021-12-04

DOI: 10.1038/s41408-021-00589-y

类型: Article

开放获取: 是

英文摘要：

MYC upregulation is associated with multidrug refractory disease in patients with multiple myeloma (MM). We, isolated patient-derived MM cells with high MYC expression and discovered that NCOR2 was down-regulated in these cells. NCOR2 is a transcriptional coregulatory protein and its role in MM remains unknown. To define the role of NCOR2 in MM, we created NCOR2 knockout human myeloma cell lines and demonstrated that NCOR2 knockout led to high MYC expression. Furthermore, NCOR2 knockout conferred resistance to pomalidomide, BET and HDAC inhibitors, independent of Cereblon (CRBN), indicating high MYC expression as a cause of multidrug resistance. Moreover, NCOR2 interacted with the nucleosome remodeling and deacetylase (NuRD) complex and repressed the expression of CD180 by directly binding to its promoter and inducing MYC expression. Next, we generated lenalidomide-resistant and pomalidomide-resistant human myeloma cell lines. Whole-exome sequencing revealed that these cell lines acquired the same exonic mutations of NCOR2. These cell lines showed NCOR2 downregulation and MYC upregulation independent of CRBN and demonstrated resistance to BET and HDAC inhibitors. Our findings reveal a novel CRBN independent molecular mechanism associated with drug resistance. Low NCOR2 expression can serve as a potential biomarker for drug resistance and needs further validation in larger prospective studies.
 

摘要翻译： 

MYC上调与多发性骨髓瘤（MM）患者的多药难治性疾病相关。我们分离出具有高MYC表达的患者来源骨髓瘤细胞，并发现这些细胞中NCOR2表达下调。NCOR2是一种转录共调节蛋白，其在多发性骨髓瘤中的作用尚不明确。为明确NCOR2在MM中的功能，我们构建了NCOR2敲除的人骨髓瘤细胞系，并证实NCOR2敲除会导致MYC高表达。此外，NCOR2敲除可导致细胞对泊马度胺、BET抑制剂和HDAC抑制剂产生耐药性，且这一过程独立于Cereblon（CRBN），表明MYC高表达是多药耐药的原因。进一步研究发现，NCOR2通过与核小体重塑和去乙酰化酶（NuRD）复合物相互作用，直接结合CD180启动子抑制其表达，从而诱导MYC表达。随后，我们构建了来那度胺和泊马度胺耐药的人骨髓瘤细胞系。全外显子组测序显示这些细胞系均获得相同的NCOR2外显子突变。这些细胞系表现出NCOR2下调和MYC上调（不依赖CRBN），并对BET及HDAC抑制剂产生耐药性。我们的研究揭示了一种与耐药相关的新型CRBN非依赖性分子机制。低表达NCOR2可作为耐药的潜在生物标志物，需在更大规模的前瞻性研究中进一步验证。

原文链接：

Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation