TY  - JOUR
A1  - Rinaldetti, Sébastien
A1  - Pfirrmann, Markus
A1  - Manz, Kirsi
A1  - Guilhot, Joelle
A1  - Dietz, Christian
A1  - Panagiotidis, Panayiotidis
A1  - Spiess, Birgit
A1  - Seifarth, Wolfgang
A1  - Fabarius, Alice
A1  - Müller, Martin
A1  - Pagoni, Maria
A1  - Dimou, Maria
A1  - Dengler, Jolanta
A1  - Waller, Cornelius F.
A1  - Brümmendorf, Tim H.
A1  - Herbst, Regina
A1  - Burchert, Andreas
A1  - Janßen, Carsten
A1  - Goebeler, Maria Elisabeth
A1  - Jost, Philipp J.
A1  - Hanzel, Stefan
A1  - Schafhausen, Philippe
A1  - Prange-Krex, Gabriele
A1  - Illmer, Thomas
A1  - Janzen, Viktor
A1  - Klausmann, Martine
A1  - Eckert, Robert
A1  - Büschel, Gerd
A1  - Kiani, Alexander
A1  - Hofmann, Wolf-Karsten
A1  - Mahon, François-Xavier
A1  - Saussele, Susanne
T1  - Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial
JF  - Clinical Lymphoma, Myeloma & Leukemia
N2  - Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc.
KW  - ABCG2
KW  - Biomarker
KW  - CML
KW  - Imatinib
KW  - Prediction
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226281
VL  - 18
IS  - 4
ER  - 
TY  - JOUR
A1  - Engel, Katharina
A1  - Rudelius, Martina
A1  - Slawska, Jolanta
A1  - Jacobs, Laura
A1  - Abhari, Behnaz Ahangarian
A1  - Altmann, Bettina
A1  - Kurutz, Julia
A1  - Rathakrishnan, Abirami
A1  - Fernández-Sáiz, Vanesa
A1  - Brunner, Andrä
A1  - Targosz, Bianca-Sabrina
A1  - Loewecke, Felicia
A1  - Gloeckner, Christian Johannes
A1  - Ueffing, Marius
A1  - Fulda, Simone
A1  - Pfreundschuh, Michael
A1  - Trümper, Lorenz
A1  - Klapper, Wolfram
A1  - Keller, Ulrich
A1  - Jost, Philipp J.
A1  - Rosenwald, Andreas
A1  - Peschel, Christian
A1  - Bassermann, Florian
T1  - USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma
JF  - EMBO Molecular Medicine
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.
KW  - B‐cell lymphoma
KW  - mitosis
KW  - ubiquitin
KW  - USP9X
KW  - XIAP
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165016
VL  - 8
ER  -