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Effects of XPO1 and FLT3 inhibition on AML
≥100×109/L. Briefly, a complete remission (CR) was defined as ≤5% bone marrow blasts, a neutrophil count ≥1.0×109/L, and a platelet count ≥100×109/L. CRi was defined as meeting all CR cri- teria except residual neutropenia (<1.0×109/L) and/or thrombocy- topenia (<100×109/L). CRp (complete remission with incomplete platelet recovery) was defined as meeting all CR criteria except thrombocytopenia (<100 ×109/L).
Statistical analyses
The Student t-test was used to analyze immunoblot and cell apoptosis data. A P-value ≤0.05 was considered statistically signif- icant. All statistical tests were two-sided and the results are expressed as the mean of triplicate samples/experiments ± stan- dard deviation/95% confidence intervals (error bars). The efficacy
of selinexor on survival was estimated by the Kaplan–Meier method,34 with log-rank statistics used to test for differences in sur- vival.
Results
Selinexor, alone, or in combination with sorafenib, exerts marked pro-apoptotic effects in human and murine FLT3-mutated acute myeloid leukemia cells
We first investigated anti-leukemia effects of selinexor on AML cells with different FLT3 mutational status. Selinexor triggered profound induction of apoptosis and inhibition of cell growth, at sub-micromolar concentra-
AD
BE
C
Figure 1. Targeting XPO1 with selinexor induces profound apoptosis in FLT3-mutated leukemic cells. Human (A) and murine (B, C) AML cell lines were treated with selinexor at the indicated concentrations for 72 h. Apoptosis induction was assessed as the percentage of annexin V–positive cells by flow cytometry. Data are the mean of three independent determinations. Error bars correspond to 95% confidence intervals. The protein levels of correlated signaling pathways (D) and phospho- rylation status (E) were determined by immunoblotting after treatment with selinexor for 24 h. GAPDH was used as a loading control.
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