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

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@article{2f972adfe5464b65bd97a4b70e6720bd,
title = "USP7 inhibition alters homologous recombination repair and targets CLL cells independent of ATM/p53 functional status",
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-resistant. 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.",
keywords = "Journal Article",
author = "Angelo Agathanggelou and Edward Smith and Nicholas Davies and Marwan Kwok and Anastasia Zlatanou and Ceri Oldreive and Jingwen Mao and {Da Costa}, David and Sina Yadollahi and Tracey Perry and Pamela Kearns and Anna Skowronska and Elliot Yates and Helen Parry and Peter Hillmen and Celine Reverdy and Remi Delansorne and Shankara Paneesha and Guy Pratt and Paul Moss and Malcolm Taylor and Grant Stewart and Tatjana Stankovic",
note = "Copyright {\textcopyright} 2017 American Society of Hematology.",
year = "2017",
month = may,
day = "11",
doi = "10.1182/blood-2016-12-758219",
language = "English",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",

}

RIS

TY - JOUR

T1 - USP7 inhibition alters homologous recombination repair and targets CLL cells independent of ATM/p53 functional status

AU - Agathanggelou, Angelo

AU - Smith, Edward

AU - Davies, Nicholas

AU - Kwok, Marwan

AU - Zlatanou, Anastasia

AU - Oldreive, Ceri

AU - Mao, Jingwen

AU - Da Costa, David

AU - Yadollahi, Sina

AU - Perry, Tracey

AU - Kearns, Pamela

AU - Skowronska, Anna

AU - Yates, Elliot

AU - Parry, Helen

AU - Hillmen, Peter

AU - Reverdy, Celine

AU - Delansorne, Remi

AU - Paneesha, Shankara

AU - Pratt, Guy

AU - Moss, Paul

AU - Taylor, Malcolm

AU - Stewart, Grant

AU - Stankovic, Tatjana

N1 - Copyright © 2017 American Society of Hematology.

PY - 2017/5/11

Y1 - 2017/5/11

N2 - 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-resistant. 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.

AB - 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-resistant. 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.

KW - Journal Article

U2 - 10.1182/blood-2016-12-758219

DO - 10.1182/blood-2016-12-758219

M3 - Article

C2 - 28495793

JO - Blood

JF - Blood

SN - 0006-4971

ER -