PDF(Pubmed)
Abstract：
Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL), but pan-Notch inhibitors showed excessive toxicity in clinical trials. To find alternative ways to target Notch signals, we investigated cell division cycle 73 (Cdc73), which is a Notch cofactor and key component of the RNA polymerase-associated transcriptional machinery, an emerging target in T-ALL. Although we confirmed previous work that CDC73 interacts with NOTCH1, we also found that the interaction in T-ALL was context-dependent and facilitated by the transcription factor ETS1. Using mouse models, we showed that Cdc73 is important for Notch-induced T-cell development and T-ALL maintenance. Mechanistically, chromatin and nascent gene expression profiling showed that Cdc73 intersects with Ets1 and Notch at chromatin within enhancers to activate expression of known T-ALL oncogenes through its enhancer functions. Cdc73 also intersects with these factors within promoters to activate transcription of genes that are important for DNA repair and oxidative phosphorylation through its gene body functions. Consistently, Cdc73 deletion induced DNA damage and apoptosis and impaired mitochondrial function. The CDC73-induced DNA repair expression program co-opted by NOTCH1 is more highly expressed in T-ALL than in any other cancer. These data suggest that Cdc73 might induce a gene expression program that was eventually intersected and hijacked by oncogenic Notch to augment proliferation and mitigate the genotoxic and metabolic stresses of elevated Notch signaling. Our report supports studying factors such as CDC73 that intersect with Notch to derive a basic scientific understanding on how to combat Notch-dependent cancers without directly targeting the Notch complex.
摘要：
激活的Notch信号在T细胞急性淋巴细胞白血病（T-ALL）中非常普遍，但pan-Notch抑制剂在临床试验中显示出过度毒性。要找到针对陷波信号的替代方法，我们研究了细胞分裂周期73（Cdc73），它是Notch辅因子，也是RNA聚合酶相关转录机制的关键组成部分，T-ALL中的新兴目标。虽然我们证实了CDC73与NOTCH1相互作用的先前工作，但我们还发现T-ALL中的相互作用是上下文依赖性的，并由转录因子ETS1促进。使用鼠标模型，我们表明Cdc73对Notch诱导的T细胞发育和T-ALL维持很重要。机械上,染色质和新生基因表达谱分析表明，Cdc73在增强子内的染色质处与Ets1和Notch相交，以通过其增强子功能激活已知T-ALL癌基因的表达。Cdc73还在启动子内与这些因子相交，以激活对DNA修复和氧化磷酸化重要的基因的转录。始终如一，Cdc73缺失导致DNA损伤和凋亡以及线粒体功能受损。NOTCH1选择的CDC73诱导的DNA修复表达程序在T-ALL中比在任何其他癌症中更高的表达。这些数据表明Cdc73可能诱导基因表达程序，该程序最终被致癌Notch交叉并劫持，以增强增殖并减轻Notch信号传导升高的基因毒性和代谢应激。我们的报告支持研究与Notch相交的CDC73等因素，以便在不直接针对Notch复合物的情况下获得有关如何对抗Notch依赖性癌症的基础科学理解。
