Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation.
Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation.
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多发性骨髓瘤患者低NCOR2水平通过MYC上调驱动多药耐药。
DOI：
10.1038/s41408-021-00589-y
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发表时间：
2021-12-04
影响因子：
12.8
通讯作者：
Raje NS
中科院分区：
文献类型：
--
作者：
Mori T;Verma R;Nakamoto-Matsubara R;Siu KT;Panaroni C;Fulzele KS;Mukaihara K;Onyewadume C;Maebius A;Kato H;Wong LP;Sadreyev RI;Scadden DT;Raje NS
MYC上调与多发性骨髓瘤（MM）患者的多药难治性疾病相关。我们分离了具有高MYC表达的患者来源的MM细胞，并发现NCOR 2在这些细胞中下调。NCOR2是一种转录共调节蛋白，其在MM中的作用尚不清楚。为了确定NCOR 2在MM中的作用，我们创建了NCOR 2敲除的人骨髓瘤细胞系，并证明NCOR 2敲除导致高MYC表达。此外，NCOR2敲除赋予对泊马度胺、BET和HDAC抑制剂的抗性，独立于Cereblon（CRBN），表明高MYC表达是多药抗性的原因。此外，NCOR 2与核小体重塑和脱乙酰酶（NuRD）复合物相互作用，并通过直接结合其启动子并诱导MYC表达来抑制CD 180的表达。接下来，我们产生了耐来那度胺和耐泊马度胺的人骨髓瘤细胞系。全外显子组测序显示，这些细胞系获得了相同的NCOR 2外显子突变。这些细胞系显示出独立于CRBN的NCOR 2下调和MYC上调，并表现出对BET和HDAC抑制剂的抗性。我们的研究结果揭示了一种新的CRBN独立的分子机制与耐药性。低NCOR 2表达可作为耐药性的潜在生物标志物，需要在更大规模的前瞻性研究中进一步验证。
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.
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影响因子：
11.4
作者：
Chng, W-J;Huang, G. F.;Chung, T. H.;Ng, S. B.;Gonzalez-Paz, N.;Troska-Price, T.;Mulligan, G.;Chesi, M.;Bergsagel, P. L.;Fonseca, R.
通讯作者：
Fonseca, R.
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi
影响因子：
64.8
作者：
Lin, RJ;Nagy, L;Evans, RM
通讯作者：
Evans, RM
影响因子：
14.9
作者：
Wang K;Li M;Hakonarson H
通讯作者：
Hakonarson H
影响因子：
8.8
作者：
Hatzi K;Jiang Y;Huang C;Garrett-Bakelman F;Gearhart MD;Giannopoulou EG;Zumbo P;Kirouac K;Bhaskara S;Polo JM;Kormaksson M;MacKerell AD Jr;Xue F;Mason CE;Hiebert SW;Prive GG;Cerchietti L;Bardwell VJ;Elemento O;Melnick A
通讯作者：
Melnick A