Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma.
Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma.
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DOI：
10.1126/scitranslmed.aab1803
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发表时间：
2015-11-04
影响因子：
17.1
通讯作者：
Marshall GM
中科院分区：
文献类型：
--
作者：
Carter DR;Murray J;Cheung BB;Gamble L;Koach J;Tsang J;Sutton S;Kalla H;Syed S;Gifford AJ;Issaeva N;Biktasova A;Atmadibrata B;Sun Y;Sokolowski N;Ling D;Kim PY;Webber H;Clark A;Ruhle M;Liu B;Oberthuer A;Fischer M;Byrne J;Saletta F;Thwe le M;Purmal A;Haderski G;Burkhart C;Speleman F;De Preter K;Beckers A;Ziegler DS;Liu T;Gurova KV;Gudkov AV;Norris MD;Haber M;Marshall GM
MYCN癌基因扩增预测儿童神经母细胞瘤的治疗耐药性我们使用MYC靶基因特征预测神经母细胞瘤预后不良，以确定组蛋白伴侣，FACILITates染色质转录（FACT），作为MYC信号的关键介导者和疾病的治疗靶点。FACT和MYCN表达在神经母细胞瘤细胞中创建了一个前向反馈回路，这对于维持相互的高表达至关重要。通过小分子箭毒蛋白化合物CBL0137的FACT抑制显著减少体内肿瘤的发生和进展。CBL0137通过阻断由遗传毒性药物引起的DNA损伤的修复而与标准化疗表现出强协同作用，从而在MYCN扩增的神经母细胞瘤细胞中创造了合成的致死环境，并提出了MYCN驱动的神经母细胞瘤的治疗策略。组蛋白伴侣FACT与MYCN在正反馈回路中起作用，并且是神经母细胞瘤的治疗靶点。
Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone, FAcilitates Chromatin Transcription (FACT), as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small molecule curaxin compound, CBL0137, markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma. Histone chaperone FACT acts in a positive feedback loop with MYCN and is a therapeutic target in neuroblastoma.
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影响因子：
11.2
作者：
Issaeva N;Thomas HD;Djureinovic T;Jaspers JE;Stoimenov I;Kyle S;Pedley N;Gottipati P;Zur R;Sleeth K;Chatzakos V;Mulligan EA;Lundin C;Gubanova E;Kersbergen A;Harris AL;Sharma RA;Rottenberg S;Curtin NJ;Helleday T
通讯作者：
Helleday T
DOI：
10.1016/j.bbagrm.2011.07.009
发表时间：
2012-03
影响因子：
4.7
作者：
Formosa, Tim
通讯作者：
Formosa, Tim
影响因子：
8.8
作者：
Garcia H;Miecznikowski JC;Safina A;Commane M;Ruusulehto A;Kilpinen S;Leach RW;Attwood K;Li Y;Degan S;Omilian AR;Guryanova O;Papantonopoulou O;Wang J;Buck M;Liu S;Morrison C;Gurova KV
通讯作者：
Gurova KV
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS
影响因子：
16.8
作者：
Burgess, Rebecca J.;Zhang, Zhiguo
通讯作者：
Zhang, Zhiguo