Cdc73 Protects Notch-Induced Leukemia Cells From DNA Damage and Mitochondrial Stress

Abstract

Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL) and accounts for about 60% of mutations in this disease. Since Notch has essential functions in normal tissue homeostasis, pan-Notch inhibitors used in clinical trials exhibited toxic effects to the patients receiving them. To find alternative ways to target Notch signals, we investigated Cell division cycle 73 (Cdc73), which is a Notch cofactor and component of the RNA polymerase-associated factor complex (Paf1c) transcriptional machinery. Transcriptional control is believed to be an attractive target in advancing T-ALL therapies. In this setting, we confirmed previous work done in a breast cancer cell line, showing that CDC73 interacts with NOTCH1 in T-ALL cell lines. However, we found that this interaction in T-ALL was context-dependent and is facilitated by the transcription factor ETS1. Using mouse models, we found that Cdc73 is important for Notch-induced T-cell development and T-ALL maintenance. Mechanistically, we identified that Cdc73, Ets1, and Notch intersect with chromatin at promoters and enhancers to activate gene expression programs that promote DNA repair and oxidative phosphorylation in the context of T-ALL. Consistently, deletion of Cdc73 induced DNA damage and impaired mitochondrial function. My project shows that Cdc73 induces these pathways through its canonical functions in regulating mRNA synthesis but can also activate oncogenes non-canonically through regulation of enhancers. This study suggests that Cdc73 might promote context-dependent gene expression programs that was eventually intersected by Notch to mitigate the genotoxic and metabolic stresses of supraphysiological Notch signaling. We also provide mechanistic support for testing inhibitors of DNA repair, oxidative phosphorylation, and transcriptional machinery as an alternative anti-leukemic therapy. In theory, inhibiting Cdc73 regulated pathways that intersect with Notch at chromatin might constitute a safer strategy to weaken Notch signals without directly targeting the entire Notch complex.