TY - JOUR
T1 - USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma
AU - Engel, Katharina
AU - Rudelius, Martina
AU - Slawska, Jolanta
AU - Jacobs, Laura
AU - Ahangarian Abhari, Behnaz
AU - Altmann, Bettina
AU - Kurutz, Julia
AU - Rathakrishnan, Abirami
AU - Fernández-Sáiz, Vanesa
AU - Brunner, Andrä
AU - Targosz, Bianca Sabrina
AU - Loewecke, Felicia
AU - Gloeckner, Christian Johannes
AU - Ueffing, Marius
AU - Fulda, Simone
AU - Pfreundschuh, Michael
AU - Trümper, Lorenz
AU - Klapper, Wolfram
AU - Keller, Ulrich
AU - Jost, Philipp J.
AU - Rosenwald, Andreas
AU - Peschel, Christian
AU - Bassermann, Florian
N1 - Publisher Copyright:
© 2016 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - B-cell lymphoma
KW - USP9X
KW - XIAP
KW - mitosis
KW - ubiquitin
UR - http://www.scopus.com/inward/record.url?scp=84980048024&partnerID=8YFLogxK
U2 - 10.15252/emmm.201506047
DO - 10.15252/emmm.201506047
M3 - Article
C2 - 27317434
AN - SCOPUS:84980048024
SN - 1757-4676
VL - 8
SP - 851
EP - 862
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 8
ER -