Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry.
Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry.
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DOI：
10.1038/s41588-018-0191-z
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发表时间：
2018-09
期刊：
影响因子：
30.8
通讯作者：
Stegmaier K
中科院分区：
文献类型：
--
作者：
Durbin AD;Zimmerman MW;Dharia NV;Abraham BJ;Iniguez AB;Weichert-Leahey N;He S;Krill-Burger JM;Root DE;Vazquez F;Tsherniak A;Hahn WC;Golub TR;Young RA;Look AT;Stegmaier K
MYCN基因扩增的儿童高危神经母细胞瘤难以有效治疗。这使人们关注肿瘤发生的肿瘤特异性基因依赖性，从而为开发新的治疗方法提供有价值的靶点。使用无偏的基因组规模CRISPR-Cas9方法来检测参与肿瘤细胞生长和存活的基因，我们确定了147个对MYCN扩增的神经母细胞瘤细胞系具有选择性的候选基因依赖性，与300多个其他人类癌细胞系相比。然后，我们使用全基因组ChIP-seq分析来证明少数必需的转录因子：MYCN，HAND 2，ISL 1，PHOX 2B，GATA 3和TBX 2，是维持MYCN扩增的神经母细胞瘤细胞状态的转录核心调控电路（CRC）的成员。为了禁用CRC，我们测试了BRD 4和CDK 7抑制剂的组合，其在体外和体内协同作用，快速下调CRC转录因子基因表达。这项研究定义了一组MYCN扩增的神经母细胞瘤中的关键依赖基因，这些基因对这种肿瘤中的细胞状态和存活至关重要。
Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively. This has focused attention on tumor-specific gene dependencies that underlie tumorigenesis and thus provide valuable targets for the development of novel therapeutics. Using unbiased genome-scale CRISPR-Cas9 approaches to detect genes involved in tumor cell growth and survival, we identified 147 candidate gene dependencies selective for MYCN-amplified neuroblastoma cell lines, compared to over 300 other human cancer cell lines. We then used genome-wide ChIP-seq analysis to demonstrate that a small number of essential transcription factors: MYCN, HAND2, ISL1, PHOX2B, GATA3, and TBX2, are members of the transcriptional core regulatory circuitry (CRC) that maintains cell state in MYCN-amplified neuroblastoma. To disable the CRC, we tested a combination of BRD4 and CDK7 inhibitors, which act synergistically, in vitro and in vivo, with rapid downregulation of CRC transcription factor gene expression. This study defines a set of critical dependency genes in MYCN-amplified neuroblastoma that are essential for cell state and survival in this tumor.
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影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
46.9
作者：
Evers, Bastiaan;Jastrzebski, Katarzyna;Bernards, Rene
通讯作者：
Bernards, Rene
影响因子：
--
作者：
Chen L;Rousseau RF;Middleton SA;Nichols GL;Newell DR;Lunec J;Tweddle DA
通讯作者：
Tweddle DA
影响因子：
46.9
作者：
Morgens DW;Deans RM;Li A;Bassik MC
通讯作者：
Bassik MC