USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma

USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma

Abstract 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...

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Main Authors: Katharina Engel, Martina Rudelius, Jolanta Slawska, Laura Jacobs, Behnaz Ahangarian Abhari, Bettina Altmann, Julia Kurutz, Abirami Rathakrishnan, Vanesa Fernández‐Sáiz, Andrä Brunner, Bianca‐Sabrina Targosz, Felicia Loewecke, Christian Johannes Gloeckner, Marius Ueffing, Simone Fulda, Michael Pfreundschuh, Lorenz Trümper, Wolfram Klapper, Ulrich Keller, Philipp J Jost, Andreas Rosenwald, Christian Peschel, Florian Bassermann
Format: Article
Language:English
Published: Springer Nature 2016-06-01
Series:EMBO Molecular Medicine
Subjects:
B‐cell lymphoma
mitosis
ubiquitin
USP9X
XIAP
Online Access:https://doi.org/10.15252/emmm.201506047
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Summary:Abstract 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 Eμ‐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.
ISSN:1757-4676
1757-4684

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