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

Abstract

// Giovanna Carr&agrave; 1 , Cristina Panuzzo 1 , Davide Torti 1,2 , Guido Parvis 2,3 , Sabrina Crivellaro 1 , Ubaldo Familiari 4 , Marco Volante 4,5 , Deborah Morena 5 , Marcello Francesco Lingua 5 , Mara Brancaccio 6 , Angelo Guerrasio 1 , Pier Paolo Pandolfi 7 , Giuseppe Saglio 1,2,3 , Riccardo Taulli 5 and Alessandro Morotti 1 1 Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Italy 2 Division of Internal Medicine - Hematology, San Luigi Gonzaga Hospital, Orbassano, Italy 3 Division of Hematology, Azienda Ospedaliera, Mauriziano, Torino, Italy 4 Division of Pathology, San Luigi Hospital, Orbassano, Italy 5 Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Italy 6 Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy 7 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Correspondence to: Alessandro Morotti, email: // Riccardo Taulli, email: // Keywords : chronic lymphocytic leukemia, USP7, PTEN, miR181, miR338 Received : June 14, 2016 Accepted : February 20, 2017 Published : March 17, 2017 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.