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

Veronika Ecker1, Lisa Brandmeier1, Martina Stumpf1

  • 1Institute 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.

Cell Reports
|October 4, 2023
PubMed

Insights

Targeting dual-specific phosphatases DUSP1 and DUSP6 effectively eliminates drug-resistant chronic lymphocytic leukemia (CLL) cells. Inhibiting these phosphatases triggers cell death pathways, offering a new therapeutic strategy for resistant CLL.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Drug-resistant chronic lymphocytic leukemia (CLL) remains a significant clinical challenge despite existing targeted therapies.
  • Mitogen-activated protein kinases (MAPKs) play a role in CLL pathogenesis, but their regulation is not fully understood.
  • Dual-specific phosphatases (DUSPs) are key regulators of MAPK signaling pathways.

Purpose of the Study:

  • To investigate the role of DUSP1 and DUSP6 in regulating MAPK activity in CLL.
  • To determine if DUSP1 and DUSP6 are potential therapeutic targets for drug-resistant CLL.

Main Methods:

  • Analysis of DUSP6 expression in CLL patient samples.
  • Genetic deletion of DUSP1 or DUSP6 in CLL cells.
  • Treatment of CLL cells with a DUSP1/6 inhibitor.
  • Global phospho-proteome analysis to assess MAPK signaling.
  • Assessment of mitochondrial reactive oxygen species (ROS) and DNA damage.
  • In vitro and in vivo studies of CLL cell survival.

Main Results:

  • High DUSP6 expression in CLL correlates with poor clinical prognosis.
  • Inhibition of DUSP1 or DUSP6, or combined DUSP1/6 inhibition, reduces CLL cell survival in vitro and in vivo.
  • DUSP1/6 inhibition leads to acute MAPK signaling activation, increased mitochondrial ROS, and DNA damage.
  • This results in apoptotic cell death in CLL cells.
  • DUSP1/6 inhibition demonstrates particular efficacy against treatment-resistant CLL.

Conclusions:

  • DUSP1 and DUSP6 are critical negative regulators of MAPK signaling in CLL.
  • Targeting DUSP1/6 is a promising strategy to overcome drug resistance in CLL.
  • Transient DUSP1/6 inhibition may offer a novel therapeutic approach for eliminating resistant CLL cells.
Keywords:
CLLCP: CancerDNA damageMAPKapoptosisphosphatases

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