Figure 5.
Combined inhibition of androgen production and ARs on high AR–expressing AML cells improves the outcome of AML. (A) Secondary transplantation was done retro-orbitally with 1° CD45.1 high AR–expressing AML donor cells to CD45.2 WT male recipients. At 1 week after transplantation, the mice were administered daily ARN509 at 10 mg/kg with or without finasteride at 20 mg/kg per day intraperitoneally for 2 weeks. The mice were euthanized at 3 weeks after transplantation; the blood, bone marrow, and spleen were sampled (n = 5-7 in each group). (B) CBC analysis of the recipient mice in panel A at the end point. (C) Spleen weights (milligram) of recipient mice in panel A at the end point. (D-G) Counts of the AML cells in the Lin- population and LICs in the bone marrow (D-E) and spleen (F-G) of recipient mice in panel A at the end point. (H) Counts of the total AML cells in the spleen of recipient mice in panel A at the end point. (I-J) qPCR analysis of AR1 (I) and AR3 (J) in AML cells derived from male (n = 10) and female (n = 10) patients. The data were normalized to male patient–derived AML cells and the 18S (RPS18) housekeeping gene. Patient samples that exhibited undetectable expressions were excluded. (K) qPCR analysis of AR1 and AR3 in AML cells derived from female (n = 3) and male (n = 3) patients. The data were presented as ΔCt. (L) A western blot showing the expression of ARs and ERs in female (1) and male (4) patient-derived AML cells. (M-O) Female (1) and male (4) patient-derived AML cells were transplanted retro-orbitally (500 000 cells per mouse) into 10 male and 10 female 11-week-old NSG mice under lethal irradiation (9.5 Gys), respectively. At day 90 after transplantation when the peripheral WBC levels reached 2000 to 3000/μL, mice were treated with or without finasteride (20 mg/kg) and ARN509 (25 mg/kg) intraperitoneally daily for 14 days. At day 127 after transplantation, these mice were euthanized, and the human cells were tested in peripheral blood (M), bone marrow (N), and spleen (O), following identification as human CD45+ cells by flow cytometry. Panels B-K, M-O, error bars represent the mean ± SEM of replicates. ∗P < .05; ∗∗P < .01, as determined by a 1-tailed unpaired Student t test. BA, basophil; EO, eosinophil; LY, lymphocyte; MO, monocyte; NE, neutrophil.

Combined inhibition of androgen production and ARs on high AR–expressing AML cells improves the outcome of AML. (A) Secondary transplantation was done retro-orbitally with 1° CD45.1 high AR–expressing AML donor cells to CD45.2 WT male recipients. At 1 week after transplantation, the mice were administered daily ARN509 at 10 mg/kg with or without finasteride at 20 mg/kg per day intraperitoneally for 2 weeks. The mice were euthanized at 3 weeks after transplantation; the blood, bone marrow, and spleen were sampled (n = 5-7 in each group). (B) CBC analysis of the recipient mice in panel A at the end point. (C) Spleen weights (milligram) of recipient mice in panel A at the end point. (D-G) Counts of the AML cells in the Lin- population and LICs in the bone marrow (D-E) and spleen (F-G) of recipient mice in panel A at the end point. (H) Counts of the total AML cells in the spleen of recipient mice in panel A at the end point. (I-J) qPCR analysis of AR1 (I) and AR3 (J) in AML cells derived from male (n = 10) and female (n = 10) patients. The data were normalized to male patient–derived AML cells and the 18S (RPS18) housekeeping gene. Patient samples that exhibited undetectable expressions were excluded. (K) qPCR analysis of AR1 and AR3 in AML cells derived from female (n = 3) and male (n = 3) patients. The data were presented as ΔCt. (L) A western blot showing the expression of ARs and ERs in female (1) and male (4) patient-derived AML cells. (M-O) Female (1) and male (4) patient-derived AML cells were transplanted retro-orbitally (500 000 cells per mouse) into 10 male and 10 female 11-week-old NSG mice under lethal irradiation (9.5 Gys), respectively. At day 90 after transplantation when the peripheral WBC levels reached 2000 to 3000/μL, mice were treated with or without finasteride (20 mg/kg) and ARN509 (25 mg/kg) intraperitoneally daily for 14 days. At day 127 after transplantation, these mice were euthanized, and the human cells were tested in peripheral blood (M), bone marrow (N), and spleen (O), following identification as human CD45+ cells by flow cytometry. Panels B-K, M-O, error bars represent the mean ± SEM of replicates. ∗P < .05; ∗∗P < .01, as determined by a 1-tailed unpaired Student t test. BA, basophil; EO, eosinophil; LY, lymphocyte; MO, monocyte; NE, neutrophil.

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