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

Veronika Ecker, Lisa Brandmeier, Martina Stumpf, Piero Giansanti, Aida Varela Moreira, Lisa Pfeuffer, Marcel H.A.M. Fens, Junyan Lu, Bernhard Kuster, Thomas Engleitner, Simon Heidegger, Roland Rad, Ingo Ringshausen, Thorsten Zenz, Clemens Martin Wendtner, Markus Müschen, Julia Jellusova, Jürgen Ruland, Maike Buchner

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Article number113017
JournalCell Reports
Volume42
Issue number10
DOIs
StatePublished - 31 Oct 2023

Keywords

  • CLL
  • CP: Cancer
  • DNA damage
  • MAPK
  • apoptosis
  • phosphatases

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