Figure 7.
Combined targeting of elevated glycolysis and mutant JAK2 activity elicited additive effects in vivo. (A) Schematic of long-term 3PO and ruxolitinib treatment. Competitive BM transplant recipient mice were induced with tamoxifen (TAM) to activate the VF and E12 mutations; 4 (for E12) or 8 weeks (for VF) later, the treatment regimen was initiated. Mice were treated with vehicle or 3PO (50 mg/kg, intraperitoneally) alone or in combination with ruxolitinib (60 mg/kg orally) every day for 8 weeks. (B) Representative pictures and weights of spleen from mice treated with vehicle or 3PO and/or ruxolitinib (n = 6 mice per genotype). (C) Weight of epididymal white adipose tissue (eWAT) in 3PO- and/or ruxolitinib-treated mice (n = 6 mice per genotype). (D) Time course of nonfasting blood glucose levels in 3PO- and/or ruxolitinib-treated mice (n = 6 mice per genotype). (E) Glucose tolerance test in 3PO- and/or ruxolitinib-treated VF (left) and E12 mice (right) (n = 6 mice per genotype). (F) Peripheral blood cell counts (upper) and frequencies of GFP+ hematopoietic cells in peripheral blood (lower) in 3PO- and/or ruxolitinib-treated mice at indicated time points (n = 6 mice per genotype). (G) Blood glucose levels in PV patients with or without cytoreductive therapy. Cytoreductive drugs were hydroxyurea (n = 19), pegylated interferon-α (n = 1), ruxolitinib (n = 3), and anagrelide (n = 1). (H) Schematic drawing depicting the metabolic changes in hematopoietic and nonhematopoietic tissues induced by expression of mutant JAK2 in hematopoietic cells. Metabolic changes and MPNs are primarily driven by the expression of mutant JAK2 in hematopoietic cells. HGD promoted proliferation of the JAK2-mutant clone and accelerated MPN phenotype, whereas ruxolitinib, 3PO, and HFD reduced the MPN manifestations. Note that some changes in metabolism were direct effects of the JAK2-mutant hematopoietic cells, whereas other changes (eg, lipolysis) were indirect consequences of the general energy crisis and/or inflammatory mediators secreted by the JAK2-mutant cells. One-way analyses of variance (ANOVAs) followed by Tukey’s multiple comparison tests were used for multiple-group comparisons, or 2-way ANOVA with subsequent Bonferroni posttest or 2-tailed unpaired t test (G) was used. All data are presented as mean ± standard error of the mean. See also supplemental Figure 8. *P < .05, **P < .01. CBC, complete blood count.

Combined targeting of elevated glycolysis and mutant JAK2 activity elicited additive effects in vivo. (A) Schematic of long-term 3PO and ruxolitinib treatment. Competitive BM transplant recipient mice were induced with tamoxifen (TAM) to activate the VF and E12 mutations; 4 (for E12) or 8 weeks (for VF) later, the treatment regimen was initiated. Mice were treated with vehicle or 3PO (50 mg/kg, intraperitoneally) alone or in combination with ruxolitinib (60 mg/kg orally) every day for 8 weeks. (B) Representative pictures and weights of spleen from mice treated with vehicle or 3PO and/or ruxolitinib (n = 6 mice per genotype). (C) Weight of epididymal white adipose tissue (eWAT) in 3PO- and/or ruxolitinib-treated mice (n = 6 mice per genotype). (D) Time course of nonfasting blood glucose levels in 3PO- and/or ruxolitinib-treated mice (n = 6 mice per genotype). (E) Glucose tolerance test in 3PO- and/or ruxolitinib-treated VF (left) and E12 mice (right) (n = 6 mice per genotype). (F) Peripheral blood cell counts (upper) and frequencies of GFP+ hematopoietic cells in peripheral blood (lower) in 3PO- and/or ruxolitinib-treated mice at indicated time points (n = 6 mice per genotype). (G) Blood glucose levels in PV patients with or without cytoreductive therapy. Cytoreductive drugs were hydroxyurea (n = 19), pegylated interferon-α (n = 1), ruxolitinib (n = 3), and anagrelide (n = 1). (H) Schematic drawing depicting the metabolic changes in hematopoietic and nonhematopoietic tissues induced by expression of mutant JAK2 in hematopoietic cells. Metabolic changes and MPNs are primarily driven by the expression of mutant JAK2 in hematopoietic cells. HGD promoted proliferation of the JAK2-mutant clone and accelerated MPN phenotype, whereas ruxolitinib, 3PO, and HFD reduced the MPN manifestations. Note that some changes in metabolism were direct effects of the JAK2-mutant hematopoietic cells, whereas other changes (eg, lipolysis) were indirect consequences of the general energy crisis and/or inflammatory mediators secreted by the JAK2-mutant cells. One-way analyses of variance (ANOVAs) followed by Tukey’s multiple comparison tests were used for multiple-group comparisons, or 2-way ANOVA with subsequent Bonferroni posttest or 2-tailed unpaired t test (G) was used. All data are presented as mean ± standard error of the mean. See also supplemental Figure 8. *P < .05, **P < .01. CBC, complete blood count.

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