The NOD/SCID Xenograft Model Provides Clinically-Relevant Insights into Glucocorticoid-Induced Gene Expression in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia

Introduction. Glucocorticoids are critical drugs used to treat acute lymphoblastic leukemia, and response to glucocorticoids is highly predictive of outcome. Here we report a study evaluating the NOD/SCID xenograft mouse model to investigate glucocorticoid-induced gene expression. Methods. NOD/SCID mice were inoculated with ALL-3, a glucocorticoid-sensitive xenograft, and when highly engrafted were randomised to either dexamethasone 15mg/kg or vehicle control IP. Cells were harvested at 0, 8, 24 or 48 hours thereafter, RNA was extracted and hybridised onto Illumina WG-6_V3 chips. Results. The 8 hour dexamethasone-treated timepoint had the highest number of significantly differentially expressed genes with minimal changes seen across the time-matched controls. Replicate analysis revealed that using data from 3 replicates instead of 4 resulted in excellent recovery scores of >0.9 at timepoints with high signal. When assessed at the level of pathways, gene expression changes in the 8 hour xenograft samples were similar to patients treated with glucocorticoids. Conclusions. The NOD/SCID xenograft mouse model provides a reproducible experimental model system in which to investigate clinically-relevant mechanisms of in vivo glucocorticoid-induced gene regulation in ALL; the 8 hour timepoint provides the highest number of significantly differentially expressed genes; time-matched controls are redundant and excellent recovery scores can be obtained with 3 replicates. At 0, 8, 24 or 48 hours, NOD/SCID xenograft mice were treated with vehicle control, or dexamethasone. We used 4 biological replicates per time point (3 at the 48hour time point), each of which went onto an Illumina HumanWG-6_V3_0_R1_11282955_A microarray. Samples from each of the 7 groups were divided across a total of 5 microarray slides