被激活的Notch信号通路在T细胞急性淋巴细胞白血病(T-ALL)中高度普遍存在，但全系Notch抑制剂在临床试验中显示出剧烈的毒性。为了寻找替代的方式来靶向Notch信号，我们研究了细胞分裂周期73（Cdc73），这是一个Notch的共因子和RNA聚合酶相关的转录机制的关键组分，是T-ALL中的一个新兴靶向物。虽然我们确认了之前的工作，即CDC73与NOTCH1之间的相互作用，但我们还发现T-ALL中的相互作用是依赖于背景情况，并通过转录因子ETS1促进。通过使用小鼠模型，我们展示了Cdc73在Notch诱导的T细胞发育和T-ALL维持中的重要性。在机制上，染色质和新生基因表达谱显示Cdc73与Ets1和Notch在增强子内部的染色质交叉，并通过其增强子功能来激活已知T-ALL致癌基因的表达。Cdc73还与这些因子在启动子区域内交叉，通过其基因体内的功能来激活与DNA修复和氧化磷酸化有关的基因的转录。一致的是，Cdc73的缺失引起了DNA损伤和凋亡，并且影响了线粒体功能。CDC73所诱导的DNA修复表达程序在T-ALL中的表达水平高于其他任何癌症。这些数据表明，Cdc73可能诱导一个基因表达程序，最终被致癌的Notch所交叉和利用，以增强增殖并减轻Notch信号传导的遗传毒性和代谢应激。我们的报告支持研究像CDC73这样与Notch存在交叉的因子，以获得如何在不直接靶向Notch复合物的情况下对抗Notch依赖性癌症的基础科学理解。版权所有©2023美国血液学学会。

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. While 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 genotoxic and metabolic stresses of elevated Notch signaling. Our report supports studying factors like CDC73 that intersect with Notch in order to derive basic science understanding on how to combat Notch-dependent cancers without directly targeting the Notch complex.Copyright © 2023 American Society of Hematology.