Genetic loss or pharmacologic degradation of JAK2 subsequent to JAK inhibitor monotherapy can overcome persistence. Deletion of Jak2 following 2 weeks of ruxolitinib treatment resulted in reduction of (A) mutant allele burden (P < .005), (B) bloods counts (P < .001), and (C) spleen weights (P < .005) compared with mice that continued to receive ruxolitinib. (Rux, n = 9; Jak2 deleted, n = 6). Deletion of JAK2 after long-term (5 weeks) of ruxolitinib treatment prevents disease relapse following cessation of treatment by reducing (D) WBC and spleen weights as well as (E) mutant allele burden in Jak2-deleted mice (n = 3). (F) Addition of PU-H71 to ruxolitinib monotherapy resulted in significant reduction in blood counts. (G) Spleen sizes were further reduced by PU-H71 therapy (P < .05, n = 4). (Data are represented at mean ± SEM). (H) Mononuclear cells from ruxolitinib-treated MPN patients were isolated and treated with 0.5 μM PU-H71 for 16 hours, which led to inhibition of JAK2 and downstream STAT-MAPK signaling.