Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

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Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

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Title: Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones
Author: Carrà, Giovanna; Panuzzo, Cristina; Torti, Davide; Parvis, Guido; Crivellaro, Sabrina; Familiari, Ubaldo; Volante, Marco; Morena, Deborah; Lingua, Marcello Francesco; Brancaccio, Mara; Guerrasio, Angelo; Pandolfi, Pier Paolo; Saglio, Giuseppe; Taulli, Riccardo; Morotti, Alessandro

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Citation: Carrà, G., C. Panuzzo, D. Torti, G. Parvis, S. Crivellaro, U. Familiari, M. Volante, et al. 2017. “Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones.” Oncotarget 8 (22): 35508-35522. doi:10.18632/oncotarget.16348. http://dx.doi.org/10.18632/oncotarget.16348.
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Abstract: Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL.
Published Version: doi:10.18632/oncotarget.16348
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482594/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33490830
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