Figure 4.
Pharmacologic inhibition of CXCR1/2 improves hematologic parameters and reticulin fibrosis in the hMPLW515L-adoptive transfer model of MF. (A) WBC counts (×103/μL), hematocrit levels (%), and PLT (×103/μL) of hMPLW515L-affected mice treated with vehicle, ruxolitinib (60 mg/kg twice daily), the CXCR1/2 inhibitor reparixin (60 mg/kg twice daily), or combination therapy at timed euthanization after 21 days of treatment. N = 6 mice per arm. ∗P < .05; ∗∗P < .01. The t test (unpaired, two-tailed) was used to compare the mean of 2 groups. Data shown represent mean ± SEM. (B) Peripheral blood mutant cell fraction by GFP percentage of treated mice. Data shown represent mean ± SEM. (C) MKs number per high powered field (HPF) observed in BM of hMPLW515L mice in response to treatment. ∗P < .05. Data shown represent mean ± SEM. (D) BM reticulin scores of hMPLW515L-diseased mice treated with either vehicle, ruxolitinib, reparixin, or combination therapy. N = 6 mice per arm. ∗P < .05; ∗∗P < .01. (E) Representative H&E and reticulin images of hMPLW515L-diseased BM treated with ruxolitinib, reparixin, or combination therapy compared with vehicle-treated mice. N = 6 mice per condition. (F) Colony-forming unit (CFU) assay demonstrating total granulocyte-macrophage progenitor (CFU-GM) colony number as a ratio to control of untreated healthy human donor (light blue) vs MF (dark blue) CD34+ cells with exogenous CXCL8 and its response to the second-generation CXCR1/2 antagonist ladarixin (10 μM) in vitro. ∗P < .05; ∗∗P < .01. Representative of duplicate experiments from 5 healthy donor (HD) and 13 individual MF cases. (G) Fold change in detectable CXCL8 levels in conditioned media (CM) elicited by either HD vs MF MKs with or without the addition of reparixin (10 μM). Representative of duplicate experiments from 3 HD and 6 individual MF cases. ∗P < .05. Data shown represent mean ± SD. (H) Total levels of CXCL8 in conditioned media of cultured stromal cells, either alone or together with healthy vs MF MKs with or without the addition of reparixin (10 μM). ∗P < .05. Data shown represent mean ± SD. Representative of duplicate experiments from 3 HD and 3 individual MF cases. Original magnification ×20 (E).

Pharmacologic inhibition of CXCR1/2 improves hematologic parameters and reticulin fibrosis in the hMPLW515L-adoptive transfer model of MF. (A) WBC counts (×103/μL), hematocrit levels (%), and PLT (×103/μL) of hMPLW515L-affected mice treated with vehicle, ruxolitinib (60 mg/kg twice daily), the CXCR1/2 inhibitor reparixin (60 mg/kg twice daily), or combination therapy at timed euthanization after 21 days of treatment. N = 6 mice per arm. ∗P < .05; ∗∗P < .01. The t test (unpaired, two-tailed) was used to compare the mean of 2 groups. Data shown represent mean ± SEM. (B) Peripheral blood mutant cell fraction by GFP percentage of treated mice. Data shown represent mean ± SEM. (C) MKs number per high powered field (HPF) observed in BM of hMPLW515L mice in response to treatment. ∗P < .05. Data shown represent mean ± SEM. (D) BM reticulin scores of hMPLW515L-diseased mice treated with either vehicle, ruxolitinib, reparixin, or combination therapy. N = 6 mice per arm. ∗P < .05; ∗∗P < .01. (E) Representative H&E and reticulin images of hMPLW515L-diseased BM treated with ruxolitinib, reparixin, or combination therapy compared with vehicle-treated mice. N = 6 mice per condition. (F) Colony-forming unit (CFU) assay demonstrating total granulocyte-macrophage progenitor (CFU-GM) colony number as a ratio to control of untreated healthy human donor (light blue) vs MF (dark blue) CD34+ cells with exogenous CXCL8 and its response to the second-generation CXCR1/2 antagonist ladarixin (10 μM) in vitro. ∗P < .05; ∗∗P < .01. Representative of duplicate experiments from 5 healthy donor (HD) and 13 individual MF cases. (G) Fold change in detectable CXCL8 levels in conditioned media (CM) elicited by either HD vs MF MKs with or without the addition of reparixin (10 μM). Representative of duplicate experiments from 3 HD and 6 individual MF cases. ∗P < .05. Data shown represent mean ± SD. (H) Total levels of CXCL8 in conditioned media of cultured stromal cells, either alone or together with healthy vs MF MKs with or without the addition of reparixin (10 μM). ∗P < .05. Data shown represent mean ± SD. Representative of duplicate experiments from 3 HD and 3 individual MF cases. Original magnification ×20 (E).

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