Figure 5.
In vivo antiproliferative effect of PLK4 inhibition. (A) In vivo CFI-400945 treatment (20 mg/kg per day) suppressed the growth, examined by in vivo bioluminescence assay, of K052 engrafted in sublethally irradiated NSG mice, compared with vehicle control. Chemotherapy (cytarabine 25 mg/kg per day + doxorubicin 1.5 mg/kg per day) did not affect the growth of K052 in mice (n = 18). Fold change of total flux refers to the flux intensity at a specific time point normalized to the flux intensity measured on day 0 of treatment. (B) Survival analysis of NSG mice engrafted with K052 showed longer survival upon in vivo CFI-400945 treatment, compared with vehicle control (n = 12). (C) In vivo CFI-400945 treatment (20 mg/kg per day) reduced the human engraftment (percentage of human CD45+, CD33+, and mouse CD45− cells in the total [human and mouse] CD45+ population) of primary TP53-mutated AML in NSG bone marrow at 28-day posttransplantation (n = 14). (D) Survival analysis of NSG mice engrafted with primary TP53-mutated AML upon in vivo CFI-400945 treatment (20 mg/kg per day) compared with vehicle control (n = 8). (E) RT-QPCR analysis showed increases in cytokines mRNA expressions in K052 upon in vivo CFI-400945 treatment (20 mg/kg per day) for 14 days (n = 12). (F) In vivo CFI-400945 treatment increased the number of macrophages (F4/80+) in NSG bone marrow compared with vehicle control (n = 12). (G) In vivo CFI-400945 (20 mg/kg per day) and anti-CD47 antibody treatment (8 mg/kg per day) showed the greatest inhibition of K052 growth, examined by in vivo bioluminescence assay, in nonirradiated NSG mice, compared with vehicle control or single treatment (CFI-400945 or anti-CD47 antibody only) (n = 40). (H) Survival analysis of NSG mice engrafted with K052 showed the longest survival upon in vivo combination treatment of CFI-400945 (20 mg/kg per day) and anti-CD47 antibody (8 mg/kg per day), compared with vehicle control or single treatment (CFI-400945 or anti-CD47 antibody only) (n = 40). (I-J) The combination treatment induced significant leukemia suppression as compared with single-arm treatment in the TP53-mutated (N = 22 mice) but not wild-type AML samples (N = 33 mice). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001.

In vivo antiproliferative effect of PLK4 inhibition. (A) In vivo CFI-400945 treatment (20 mg/kg per day) suppressed the growth, examined by in vivo bioluminescence assay, of K052 engrafted in sublethally irradiated NSG mice, compared with vehicle control. Chemotherapy (cytarabine 25 mg/kg per day + doxorubicin 1.5 mg/kg per day) did not affect the growth of K052 in mice (n = 18). Fold change of total flux refers to the flux intensity at a specific time point normalized to the flux intensity measured on day 0 of treatment. (B) Survival analysis of NSG mice engrafted with K052 showed longer survival upon in vivo CFI-400945 treatment, compared with vehicle control (n = 12). (C) In vivo CFI-400945 treatment (20 mg/kg per day) reduced the human engraftment (percentage of human CD45+, CD33+, and mouse CD45− cells in the total [human and mouse] CD45+ population) of primary TP53-mutated AML in NSG bone marrow at 28-day posttransplantation (n = 14). (D) Survival analysis of NSG mice engrafted with primary TP53-mutated AML upon in vivo CFI-400945 treatment (20 mg/kg per day) compared with vehicle control (n = 8). (E) RT-QPCR analysis showed increases in cytokines mRNA expressions in K052 upon in vivo CFI-400945 treatment (20 mg/kg per day) for 14 days (n = 12). (F) In vivo CFI-400945 treatment increased the number of macrophages (F4/80+) in NSG bone marrow compared with vehicle control (n = 12). (G) In vivo CFI-400945 (20 mg/kg per day) and anti-CD47 antibody treatment (8 mg/kg per day) showed the greatest inhibition of K052 growth, examined by in vivo bioluminescence assay, in nonirradiated NSG mice, compared with vehicle control or single treatment (CFI-400945 or anti-CD47 antibody only) (n = 40). (H) Survival analysis of NSG mice engrafted with K052 showed the longest survival upon in vivo combination treatment of CFI-400945 (20 mg/kg per day) and anti-CD47 antibody (8 mg/kg per day), compared with vehicle control or single treatment (CFI-400945 or anti-CD47 antibody only) (n = 40). (I-J) The combination treatment induced significant leukemia suppression as compared with single-arm treatment in the TP53-mutated (N = 22 mice) but not wild-type AML samples (N = 33 mice). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001.

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