Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression.

Autor:	Ecker V; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany., Brandmeier L; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany., Stumpf M; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany., Giansanti P; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany; Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM), Freising, Bavaria, Germany; Bavarian Center for Biomolecular Mass Spectrometry at the University hospital rechts der Isar (BayBioMS@MRI), Technical University of Munich, Munich, Germany., Moreira AV; Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands., Pfeuffer L; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany., Fens MHAM; Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands., Lu J; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Kuster B; Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM), Freising, Bavaria, Germany; Bavarian Center for Biomolecular Mass Spectrometry at the University hospital rechts der Isar (BayBioMS@MRI), Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Munich Partner Site, Munich, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany., Engleitner T; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, 81675 Munich, Germany., Heidegger S; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany; Department of Medicine III, School of Medicine, Technical University of Munich, Munich, Germany., Rad R; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany; German Cancer Consortium (DKTK), Munich Partner Site, Munich, Germany; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, 81675 Munich, Germany., Ringshausen I; Wellcome Trust/MRC Cambridge Stem Cell Institute and Department of Haematology, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AH, UK., Zenz T; Department of Medical Oncology and Hematology, University Hospital and University of Zurich, 8091 Zurich, Switzerland., Wendtner CM; Munich Clinic Schwabing, Academic Teaching Hospital, Ludwig-Maximilian University (LMU), Munich, Germany., Müschen M; Center of Molecular and Cellular Oncology, Yale School of Medicine, 300 George Street, New Haven, CT 06520, USA., Jellusova J; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany., Ruland J; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany; German Cancer Consortium (DKTK), Munich Partner Site, Munich, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany., Buchner M; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany; TranslaTUM - Central Institute for Translational Cancer Research, Technische Universität München, 81675 Munich, Germany. Electronic address: maike.buchner@tum.de.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Oct 31; Vol. 42 (10), pp. 113017. Date of Electronic Publication: 2023 Oct 04.
DOI:	10.1016/j.celrep.2023.113017
Abstrakt:	Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells. Competing Interests: Declaration of interests S.H. is an employee of and holds equity interest in Roche/Genentech. S.H. has received research funding from Bristol Myers-Squibb and Novartis. S.H. has been a consultant for Bristol Myers-Squibb, Novartis, Merck, Abbvie, and Roche. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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