DUSP1 deletion is synthetic lethal to JAK2V617F induced MPN

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.