USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma.
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.
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Katharina
K
Engel
Institute of Pathology and Comprehensive Cancer Center Mainfranken, Universität Würzburg, Würzburg, Germany.
Martina
M
Rudelius
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Jolanta
J
Slawska
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Laura
L
Jacobs
Institut für Experimentelle Tumorforschung in der Pädiatrie, Goethe-Universität Frankfurt, Frankfurt am Main, Germany.
Behnaz
B
Ahangarian Abhari
Institute for Medical Informatics, Statistics and Epidemiology, Universität Leipzig, Leipzig, Germany.
Bettina
B
Altmann
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Julia
J
Kurutz
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Abirami
A
Rathakrishnan
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Vanesa
V
Fernández-Sáiz
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Andrä
A
Brunner
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Bianca-Sabrina
BS
Targosz
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Felicia
F
Loewecke
Eberhard-Karls-Universität Tübingen, Institute for Ophthalmic Research, Medical Proteome Center, Tübingen, Germany German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Christian Johannes
CJ
Gloeckner
Eberhard-Karls-Universität Tübingen, Institute for Ophthalmic Research, Medical Proteome Center, Tübingen, Germany.
Marius
M
Ueffing
Institut für Experimentelle Tumorforschung in der Pädiatrie, Goethe-Universität Frankfurt, Frankfurt am Main, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Simone
S
Fulda
Department of Medicine I, Saarland University Medical School, Homburg (Saar), Germany.
Michael
M
Pfreundschuh
Department of Hematology and Oncology, Georg-August-Universität Göttingen, Göttingen, Germany.
Lorenz
L
Trümper
Institute of Pathology, Haematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
Wolfram
W
Klapper
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ulrich
U
Keller
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
Philipp J
0000-0003-2454-0362
PJ
Jost
Institute of Pathology and Comprehensive Cancer Center Mainfranken, Universität Würzburg, Würzburg, Germany.
Andreas
A
Rosenwald
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Christian
C
Peschel
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, München, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany florian.bassermann@tum.de.
Florian
0000-0003-4435-2609
F
Bassermann
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004351:Drug Resistance; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology*; D051379:Mice; D008938:Mitosis; D011499:Protein Processing, Post-Translational; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D000970:Antineoplastic Agents; C506234:USP9X protein, human; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D043222:Ubiquitin Thiolesterase
B‐cell lymphoma; USP9X; XIAP; mitosis; ubiquitin