Negative Feedback Regulation of MAPK Signaling Is an Important Driver of CLL Progression

Abstract Despite several potent targeted treatments for chronic lymphocytic leukemia (CLL), the clinical challenge of treating drug-resistant disease is emerging. In this study, we discovered that the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate Mitogen-activated protein kinases (MAPK) and thus counterbalance excessive MAPK activity to prevent apoptosis in CLL. We show that DUSP1 and DUSP6 are widely expressed in CLL and high expression of DUSP6 in CLL correlates with a poor clinical prognosis, which may reflect high levels of MAPK activity. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small molecule are toxic for CLL cells in vitro and in vivo . Analyzing downstream effects using global phospho-proteome approaches, we observed that acute activation of MAPK signaling by DUSP1/6 inhibition induces DNA damage response and thereby apoptotic cell death in CLL cells. This cell death is mediated by CHK kinases and can function independent of p53 and ATM, both effectors of DNA damage response, which are frequently deleted in CLL. Finally, we observed that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising novel treatment concept to eliminate drug-resistant CLL cells.