Fig. 4: Dual JAK2 and ERK1/2 inhibition by ruxolitinib/LTT462 enhances therapeutic efficacy in a Jak2V617F MPN preclinical model. | Leukemia

Fig. 4: Dual JAK2 and ERK1/2 inhibition by ruxolitinib/LTT462 enhances therapeutic efficacy in a Jak2V617F MPN preclinical model.

From: Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy

Fig. 4

Jak2V617F CD45.2 and Jak2 WT CD45.1 bone marrow (BM) was mixed at 1:1 ratio and transplanted into CD45.1 C57BL/6 recipient mice. Results for 2 weeks of treatment are shown (see Supplementary Fig. 8 for 4 week treatment). A Erythrocytosis reflected by increased hematocrit was effectively corrected by combined JAK2/ERK1/2 inhibition with LTT462 at 75 mg/kg qd and ruxolitinib at 60 mg/kg bid (n = 6–8/group, left panel). Splenomegaly was moderated by treatment with LTT462 at 75 mg/kg qd or ruxolitinib at 60 mg/kg bid, and LTT462 enhanced ruxolitinib effects when both agents were combined (right panel). B Dual ruxolitinib/LTT462 significantly improved control of the Jak2V617F clone reflected by CD45.2/CD45 chimerism in BM as compared to ruxolitinib monotherapy. C Dual ruxolitinib/LTT462 effectively inhibited the activation of ERK1/2 downstream target RSK3 as shown by reduced phosphorylated RSK3 (pRSK3). Data are presented as mean ± SD. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 by one-way ANOVA.

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