Figure 7.
LY2784544 selectively reduces Ba/F3-JAK2V617F-GFP-positive tumor cell burden in mice after oral treatment. LY2784544 was administered orally, twice daily for 8 days at the specified doses, starting 1 day before intravenous infusion of tumor cells, with six mice per dosage group, and a six-mouse vehicle control group. Standard error is indicated by the error bars with statistically significant inhibition, as defined as P<0.05 using Dunnett's test, indicated by an asterisk (*). (a) LY2784544 significantly reduces Ba/F3-JAK2V617F-GFP tumor burden after treatment for 8 days. Ba/F3-JAK2V617F-GFP-positive cells in spleens were isolated and analyzed by flow cytometry. LY2784544 significantly reduced the percentage of Ba/F3-JAK2V617F-GFP-positive cells at 40 mg/kg (P=8 × 10−4) and 80 mg/kg (P=8 × 10−7). (b) LY2784544 shows no effect on erythroid progenitors. Left: representative FACS histograms showing no effect of LY2784544 (5–80 mg/kg) on CD71/Ter119 double positive cell populations (gated), however, tumor-bearing animals displayed a significantly reduced number of erythroid progenitors, as demonstrated in animals with no tumors versus vehicle controls. Right: quantification of CD71+/Ter119 FACS data. (c) LY2784544 shows no effect on peripheral blood reticulocytes in all treated groups. (d) LY2784544 restores the platelet count to levels observed in non-tumor-bearing mice. Peripheral blood platelet count in the tumor-bearing vehicle control animals was significantly reduced compared with non-tumor-bearing animals (P=6 × 10−5). Treatment with LY2784544 at 80 mg/kg significantly reversed the tumor-dependent suppression of platelet counts (P=1 × 10−6), returning the platelet count to levels observed in non-tumor-bearing mice. Ba/F3, murine pro-B-cells; CD, cluster of differentiation; FACS, fluorescence-activated cell sorting; GFP, green fluorescent protein; JAK, janus kinase.