MAPK-negative feedback regulation confers dependence to JAK2<sup>V617F</sup> signaling.

Overview

Despite significant advances in developing selective JAK2 inhibitors, JAK2 kinase inhibitor (TKI) therapy is ineffective in suppressing the disease. Reactivation of compensatory MEK-ERK and PI3K survival pathways sustained by inflammatory cytokine signaling causes treatment failure. Concomitant inhibition of MAPK pathway and JAK2 signaling showed improved in vivo efficacy compared to JAK2 inhibition alone but lacked clonal selectivity. We hypothesized that cytokine signaling in JAK2^V617F induced MPNs increases the apoptotic threshold that causes TKI persistence or refractoriness. Here, we show that JAK2^V617F and cytokine signaling converge to induce MAPK negative regulator, DUSP1. Enhanced DUSP1 expression blocks p38 mediated p53 stabilization. Deletion of Dusp1 increases p53 levels in the context of JAK2^V617F signaling that causes synthetic lethality to Jak2^V617F expressing cells. However, inhibition of Dusp1 by a small molecule inhibitor (BCI) failed to impart Jak2^V617F clonal selectivity due to pErk1/2 rebound caused by off-target inhibition of Dusp6. Ectopic expression of Dusp6 and BCI treatment restored clonal selectively and eradicated the Jak2^V617F cells. Our study shows that inflammatory cytokines and JAK2^V617F signaling converge to induce DUSP1, which downregulates p53 and establishes a higher apoptotic threshold. These data suggest that selectively targeting DUSP1 may provide a curative response in JAK2^V617F-driven MPN.