ORCID Profile
0000-0001-5682-0938
Current Organisation
Management and Science University
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Publisher: American Association for Cancer Research (AACR)
Date: 2019
DOI: 10.1158/1078-0432.CCR-18-1740
Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient s les, and xenograft models. We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.TOX.2021.153053
Abstract: Toxicity testing relies heavily on animals, especially rodents as part of the non-clinical laboratory testing of substances. However, the use of mammalians and the number of animals employed in research has become a concern for institutional ethics committees. Toxicity testing involving rodents and other mammals is laborious and costly. Alternatively, non-rodent models are used as replacement, as they have less ethical considerations and are cost-effective. Of the many alternative models that can be used as replacement models, which ones can be used in predictive toxicology? What is the correlation between these models and rodents? Are there standardized protocols governing the toxicity testing of these commonly used predictive models? This review outlines the common alternative animal models for predictive toxicology to address the importance of these models, the challenges, and their standard testing protocols.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Suresh Kumar.