The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC-induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X-linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B-cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event-free survival in patients treated with spindle poison-containing chemotherapy. Accordingly, aggressive B-cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Emu-Myc lymphoma model. Together, we specify the USP9X-XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B-cell lymphoma.
PubMed ID: 27317434
Projects: German Lymphoma Alliance (GLA)
Journal: EMBO Mol Med
Human Diseases: B-cell lymphoma
Citation: EMBO Mol Med. 2016 Aug 1;8(8):851-62. doi: 10.15252/emmm.201506047. Print 2016 Aug.
Date Published: 19th Jun 2016
Authors: Christoph Engel, M. Rudelius, J. Slawska, L. Jacobs, B. Ahangarian Abhari, Bettina Altmann, J. Kurutz, A. Rathakrishnan, V. Fernandez-Saiz, A. Brunner, B. S. Targosz, F. Loewecke, C. J. Gloeckner, M. Ueffing, S. Fulda, M. Pfreundschuh, L. Trumper, W. Klapper, U. Keller, P. J. Jost, A. Rosenwald, C. Peschel, F. Bassermann
Created: 17th Apr 2019 at 12:39
Last updated: 16th May 2019 at 14:27