Negative feedback regulation of MAPK signaling is an important driver of CLL progression

Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study was to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate Mitogen-activated protein kinases (MAPK) and thus counterbalance excessive MAPK activity. We showed 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 reduced CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observed that acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial ROS and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observed that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising unexpected treatment concept to eliminate drug-resistant CLL cells.