Promising New Strategies to Target Gene Regulatory Factors in T-Cell Acute Lymphoblastic Leukemia

Ott, Christopher J.

doi:10.2217/ijh.14.44

Cited by 2 publications

(1 citation statement)

References 18 publications

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“…Thus, future studies on the CDC73 interactome are needed to find ways to selectively target CDC73 functions, such as through inhibitors of protein-protein interactions. Further, our study supports the notion that T-ALL cells are a cancer type that is sensitive to inhibition of general transcriptional machinery, which had once been considered to be too toxic to block given its vital functions in normal cells (Ott 2014). Previous work showed that T-ALL cells are highly dependent on cofactors of Pol II, such as CDK7, MYC, and BRD4 (Bisgrove et al 2007;Rahl et al 2010;Kwiatkowski et al 2014;Roderick et al 2014).…”

Section: Discussionsupporting

confidence: 85%

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress

Melnick

Liang

Liu

et al. 2023

Preprint

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Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL) but pan-Notch inhibitors were toxic in clinical trials. To find alternative ways to target Notch signals, we investigated Cell division cycle 73 (Cdc73), which is a Notch cofactor and component of transcriptional machinery, a potential 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 lymphoid transcription factor ETS1. Using mouse models, we showed that Cdc73 is important for Notch-induced T-cell development and T-ALL maintenance. Mechanistically, Cdc73, Ets1, and Notch intersect chromatin at promoters and enhancers to activate oncogenes and genes that are important for DNA repair and oxidative phosphorylation. Consistently, Cdc73 deletion in T-ALL cells induced DNA damage and impaired mitochondrial function. Our data suggests that Cdc73 might promote a gene expression program that was eventually intersected by Notch to mitigate the genotoxic and metabolic stresses of elevated Notch signaling. We also provide mechanistic support for testing inhibitors of DNA repair, oxidative phosphorylation, and transcriptional machinery. Inhibiting pathways like Cdc73 that intersect with Notch at chromatin might constitute a strategy to weaken Notch signals without directly targeting the Notch complex.

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Section: Discussionsupporting

confidence: 85%

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress

Melnick

Liang

Liu

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress

Melnick,

Mullin,

Lin

et al. 2023

Blood

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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.

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Promising New Strategies to Target Gene Regulatory Factors in T-Cell Acute Lymphoblastic Leukemia

Cited by 2 publications

References 18 publications

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress

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