Reversal of steroid resistance by IL7R signaling inhibitors.

<p>Activity status of IL7R signaling molecules by Western blot analysis in SUPT1 cells expressing (A) JAK1^T901A or (B) wild-type AKT that are exposed to ruxolitinib (2 μM), CI1040 (10 μM), MK2206 (2 μM), or the CI1040/MK2206 combination for 24 h compared to non-induced and doxycycline-induced controls. (C and D) SUPT1 or P12 Ichikawa (D, middle panel) T cell acute lymphoblastic leukemia cell response curves following 72-h exposure to serial dilutions of prednisolone (triplicate experiments ± standard deviation) without (−Dox, grey circles) or with (+Dox, open red circles) induction of (C) IL7R^RFCPH or (D) AKT. The effect of 2 μM ruxolitinib (left panels), 10 μM CI1040 (middle panels), and 2 μM MK2206 (right panels) on the steroid response under doxycycline-induced conditions are shown (open blue triangles). (E–I) Mean survival (triplicate experiments ± standard deviation) of SUPT1 lines expressing wild-type or mutant IL7R signaling molecules following 72-h treatment with prednisolone (250 μg/ml) in the absence (open red bars) or presence (open blue bars) of (E) ruxolitinib, (F) CI1040, (G) MK2206, (H) the combination of CI1040/MK2206, or (I) GSK3 inhibitor IX. Steroid-sensitive and -resistant panels are indicated. For each experiment, the mean survival for all non-induced (−Dox) SUPT1 lines that are exposed to prednisolone (red, grey-filled bar) or prednisolone plus inhibitor (blue, grey-filled bar) is shown as a control. See also <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002200#pmed.1002200.s008" target="_blank">S8 Fig</a>. Dox, doxycycline; inh., inhibitor; Pred, prednisolone; Rux, ruxolitinib.