American Society of Hematology

Figure 5

$Figure 5. ATRA and sorafenib improve disease progression of AML and survival in mouse xenograft models. (A-E) NOG mice received 1 × 105 Molm14 cells via tail vain injection on day 0, and randomly assigned cohorts of mice (n = 10) were administered the following compounds on day 3 to day 24 posttransplant: sorafenib (8 mg/kg daily), ATRA (5 mg/kg daily), sorafenib + ATRA (Combo, 8 and 5 mg/kg, respectively) or vehicle, all via oral gavage. On day 24, n = 3 mice were sacrificed at random from each cohort and analyzed for disease progression. Remaining mice (n = 7 per cohort) were monitored for survival. (A) PB engraftment on day 24, represented by percentage human CD45+ (hCD45+) cells out of total of mouse CD45+ (mCD45+) and hCD45+ cells. Data represent average of n = 3 mice per cohort ± SD (*P < .05, **P < .01). (B) BM engraftment on day 24, represented as in panel A (*P < .05, **P < .01). (C) BM cellular morphology on day 24 by Wright-Giemsa staining at ×100 magnification. Reduction in fraction of leukemic cells and increased evidence of atypical monocytic differentiation is apparent in BM cells of combo-treated mice. Red scale bar represents 10 µm. Data are representative of n = 3 mice per cohort. (D) Kaplan-Meier survival of mouse cohorts (n = 7 each), indicating median survival of vehicle (25 days), ATRA (30 days), sorafenib (32 days), and combo (42 days) treated mice (***P < .001). (E-H) NOG mice received 1 × 106 AML7842 or AML3878 primary cells via tail vain injection, and randomly assigned cohorts of mice (n = 4-7) were treated as described above for 3 weeks. At end of treatment, mice were sacrificed and analyzed for disease progression. (E) BM engraftment at end of treatment, represented as in panel A. Data represent average of n = 4-7 mice per cohort ± SD (*P < .05, **P < .01, ***P < .001). (F) BM CD14 expression in AML7842 recipient mice, represented by MFI of human CD14 in hCD45+ cells. Data represent average of n = 4 mice per cohort ± SD (*P < .05, **P < .01). (G-H) BM cellular morphology at end of treatment of (G) AML7842 and (H) AML3878 recipient mice by Wright-Giemsa staining at ×100 magnification. Reduction in fraction of leukemic cells and increased evidence of granulocytic and monocytic differentiation is apparent in BM cells of combo-treated mice. Yellow arrow indicates cell with iron particle deposition. Red scale bar represents 10 µm. Data are representative of n = 4-7 mice per cohort.$

ATRA and sorafenib improve disease progression of AML and survival in mouse xenograft models. (A-E) NOG mice received 1 × 10⁵ Molm14 cells via tail vain injection on day 0, and randomly assigned cohorts of mice (n = 10) were administered the following compounds on day 3 to day 24 posttransplant: sorafenib (8 mg/kg daily), ATRA (5 mg/kg daily), sorafenib + ATRA (Combo, 8 and 5 mg/kg, respectively) or vehicle, all via oral gavage. On day 24, n = 3 mice were sacrificed at random from each cohort and analyzed for disease progression. Remaining mice (n = 7 per cohort) were monitored for survival. (A) PB engraftment on day 24, represented by percentage human CD45⁺ (hCD45⁺) cells out of total of mouse CD45⁺ (mCD45⁺) and hCD45⁺ cells. Data represent average of n = 3 mice per cohort ± SD (*P < .05, **P < .01). (B) BM engraftment on day 24, represented as in panel A (*P < .05, **P < .01). (C) BM cellular morphology on day 24 by Wright-Giemsa staining at ×100 magnification. Reduction in fraction of leukemic cells and increased evidence of atypical monocytic differentiation is apparent in BM cells of combo-treated mice. Red scale bar represents 10 µm. Data are representative of n = 3 mice per cohort. (D) Kaplan-Meier survival of mouse cohorts (n = 7 each), indicating median survival of vehicle (25 days), ATRA (30 days), sorafenib (32 days), and combo (42 days) treated mice (***P < .001). (E-H) NOG mice received 1 × 10⁶ AML7842 or AML3878 primary cells via tail vain injection, and randomly assigned cohorts of mice (n = 4-7) were treated as described above for 3 weeks. At end of treatment, mice were sacrificed and analyzed for disease progression. (E) BM engraftment at end of treatment, represented as in panel A. Data represent average of n = 4-7 mice per cohort ± SD (*P < .05, **P < .01, ***P < .001). (F) BM CD14 expression in AML7842 recipient mice, represented by MFI of human CD14 in hCD45⁺ cells. Data represent average of n = 4 mice per cohort ± SD (*P < .05, **P < .01). (G-H) BM cellular morphology at end of treatment of (G) AML7842 and (H) AML3878 recipient mice by Wright-Giemsa staining at ×100 magnification. Reduction in fraction of leukemic cells and increased evidence of granulocytic and monocytic differentiation is apparent in BM cells of combo-treated mice. Yellow arrow indicates cell with iron particle deposition. Red scale bar represents 10 µm. Data are representative of n = 4-7 mice per cohort.

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