Combination of JAK2 and HSP90 inhibition is more efficacious than JAK inhibitor monotherapy. (A) Combination of ruxolitinib and PU-H71 resulted in JAK2 degradation and inhibition of downstream signaling in splenocytes of MPLW515L-transduced mice (all lanes were run on the same gel). After 2 weeks of drug treatment, the ruxolitinib and PU-H71 combination arm had significantly lower (B) WBC and (C) Plt compared with ruxolitinib alone (P < .0001, n = 10). (D) Spleen size in the combination arm was also lower. (E) Improved histopathology and reduction in BM fibrosis in mice treated with combination of JAK and HSP90 inhibitors. (F) After 4 weeks of drug treatment, the combination group that had ruxolitinib dose increased to 90 mg/kg for 2 weeks (Rux90*+PU-H71) had lowest blood counts and spleen sizes compared with ruxolitinib alone. (Data are represented at mean ± SEM; n = 4).