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USP7 inhibition alters homologous recombination repair and targets CLL cells independent of ATM/p53 functional status.

Agathanggelou, Angelo and Smith, Edward and Davies, Nicholas J and Kwok, Marwan and Zlatanou, Anastasia and Oldreive, Ceri E and Mao, Jingwen and Da Costa, David and Yadollahi, Sina and Perry, Tracey and Kearns, Pamela and Skowronska, Anna and Yates, Elliot and Parry, Helen and Hillmen, Peter and Reverdy, Celine and Delansorne, Remi and Paneesha, Shankara and Pratt, Guy and Moss, Paul and Taylor, A Malcolm R and Stewart, Grant S and Stankovic, Tatjana (2017) USP7 inhibition alters homologous recombination repair and targets CLL cells independent of ATM/p53 functional status. Blood. ISSN 1528-0020. This article is available to all HEFT staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their HEFT Athens login IDs

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Official URL: http://www.bloodjournal.org/content/early/2017/05/...

Abstract

The role of the deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whilst previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we have recently shown that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase, RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome. We demonstrate that USP7 is upregulated in CLL cells and its loss or inhibition disrupts homologous recombination repair (HRR). Consequently, USP7 inhibition induces significant tumor cell killing independent of ATM and p53 through the accumulation of genotoxic levels of DNA damage. Moreover, USP7 inhibition sensitizes p53-defective, chemoresistant CLL cells to clinically achievable doses of HRR-inducing chemotherapeutic agents in vitro and in vivo in a murine xenograft model. Together, these results identify USP7 as a promising therapeutic target for the treatment of hematological malignancies with DDR defects, where ATM/p53-dependent apoptosis is compromised.

Item Type: Article
Additional Information: This article is available to all HEFT staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their HEFT Athens login IDs
Subjects: WH Haemic and lymphatic systems. Haematology
Divisions: Planned IP Care > Oncology and Clinical Haematology
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Depositing User: Mrs Caroline Tranter
Date Deposited: 09 Jun 2017 10:57
Last Modified: 09 Jun 2017 10:57
URI: http://www.repository.heartofengland.nhs.uk/id/eprint/1403

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