Fig. 2: Inhibition of mevalonate pathway induces antileukemic effects.
A Scheme representing the cholesterol pathway and its inhibition with different small molecules. CRISPR/Cas9 t(4;11) cells and CD34+ control cells (ctrl) were treated for 7 days with DMSO (0 µM) or increasing concentrations of B RORγ antagonist XY018, C SREBP2 inhibitor fatostatin (FS) or D HMGCR inhibitor atorvastatin (ATV). The percentage of living cells (annexin V−, propidium iodide [PI]−) was evaluated with flow cytometry and IC50 values were interpolated from a four-parameter logistic model constrained to 0 and 1 in GrapdhPad Prism. Cells were counted with trypan blue and absolute cell count was evaluated for different inhibitor concentrations (0, 10, 15 µM) for E XY018, F FS and G ATV for a total of 7 days. Experiments were performed with three independent donors (n = 3) in technical triplicates and dots represent the mean ± SD. One-way ANOVA. *p < 0.05. ns not significant. H Heat map display of fold changes (in log2) in genes of cholesterol homeostasis in CRISPR/Cas9 t(4;11) cells treated with 15 µM of each small molecule or 5 nM cytarabine for 7 days. The expression of indicated genes was measured by RT-qPCR for which DMSO-treated cells were set as 1. Experiments were performed with three independent donors (n = 3) in technical duplicates. One-way ANOVA. *p < 0.05.
