DUSP1 deletion is synthetic lethal to JAK2V617F induced MPN

Despite significant advances in developing selective JAK2 tyrosine kinase inhibitors (TKI), its clinical efficacy is not durable. Reactivation of compensatory MEK-ERK and PI3K survival pathways sustained by inflammatory cytokine signaling causes treatment failure. Here, we show that JAK2V617F and cytokine signaling converge to induce MAPK negative-regulator, DUSP1, which accelerates P53 turnover by blocking P38 mediated phosphorylation and stabilization. Deletion of Dusp1 increases P53 phosphorylation and stabilization that results in selective demise of Jak2V617F clones. However, inhibition of Dusp1 by a small molecule inhibitor (BCI) failed to impart Jak2V617F 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 Jak2V617F cells. Our study shows that inflammatory cytokines and JAK2V617F signaling converge to induce Dusp1, which downregulates P53 that results in a higher apoptotic threshold. These data provide evidence that selectively targeting of DUSP1 will impart a curative response in JAK2V617F-driven MPN