2. Academic Validation
  3. Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

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

  • Cell Rep. 2023 Oct 3;42(10):113017. doi: 10.1016/j.celrep.2023.113017.
Veronika Ecker 1,  Lisa Brandmeier 1,  Martina Stumpf 1,  Piero Giansanti 2,  Aida Varela Moreira 3,  Lisa Pfeuffer 1,  Marcel H A M Fens 4,  Junyan Lu 5,  Bernhard Kuster 6,  Thomas Engleitner 7,  Simon Heidegger 8,  Roland Rad 9,  Ingo Ringshausen 10,  Thorsten Zenz 11,  Clemens-Martin Wendtner 12,  Markus Müschen 13,  Julia Jellusova 1,  Jürgen Ruland 14,  Maike Buchner 15
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 4 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.
  • 5 European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • 6 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.
  • 7 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.
  • 8 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.
  • 9 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.
  • 10 Wellcome Trust/MRC Cambridge Stem Cell Institute and Department of Haematology, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AH, UK.
  • 11 Department of Medical Oncology and Hematology, University Hospital and University of Zurich, 8091 Zurich, Switzerland.
  • 12 Munich Clinic Schwabing, Academic Teaching Hospital, Ludwig-Maximilian University (LMU), Munich, Germany.
  • 13 Center of Molecular and Cellular Oncology, Yale School of Medicine, 300 George Street, New Haven, CT 06520, USA.
  • 14 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.
  • 15 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: [email protected].
PMID: 37792532 DOI: 10.1016/j.celrep.2023.113017
Abstract

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.

Keywords

CLL; CP: Cancer; DNA damage; MAPK; apoptosis; phosphatases.

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