Evaluation of the NOD/SCID xenograft model for glucocorticoid-regulated gene expression in childhood B-cell precursor acute lymphoblastic leukemia

• Published in: BMC genomics Vol. 12; no. 1; p. 565
• Main Authors: Bhadri, Vivek A, Cowley, Mark J, Kaplan, Warren, Trahair, Toby N, Lock, Richard B
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 17-11-2011; BioMed Central; BMC
• Subjects: Acute lymphatic leukemia; Acute lymphocytic leukemia; Animal models; Animals; Apoptosis; B cells; Cancer; Chemotherapy; Children; Corticosteroids; Data processing; Dexamethasone; Dexamethasone - pharmacology; Disease Models, Animal; Drugs; Female; Gene expression; Gene Expression Regulation, Leukemic - drug effects; Gene regulation; Genetic aspects; Genomics; Glucocorticoids; Glucocorticoids - pharmacology; Lymphocytes B; Medical research; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Physiological aspects; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Prednisolone; Proteins; Spleen; Studies; Time Factors; Transcriptome; Xenografts; Australia
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/1471-2164-12-565

Glucocorticoids such as prednisolone and dexamethasone are critical drugs used in multi-agent chemotherapy protocols used to treat acute lymphoblastic leukemia (ALL), and response to glucocorticoids is highly predictive of outcome. The NOD/SCID xenograft mouse model of ALL is a clinically relevant model in which the mice develop a systemic leukemia which retains the fundamental biological characteristics of the original disease. Here we report a study evaluating the NOD/SCID xenograft mouse model to investigate glucocorticoid-induced gene expression. Cells from a glucocorticoid-sensitive xenograft derived from a child with B-cell precursor ALL were inoculated into NOD/SCID mice. When highly engrafted the mice were randomized into groups of 4 to receive dexamethasone 15 mg/kg by intraperitoneal injection or vehicle control. Leukemia cells were harvested from mice spleens at 0, 8, 24 or 48 hours thereafter, and gene expression analyzed on Illumina WG-6_V3 chips, comparing all groups to time 0 hours.
The 8 hour dexamethasone-treated timepoint had the highest number of significantly differentially expressed genes, with fewer observed at the 24 and 48 hour timepoints, and with minimal changes seen across the time-matched controls. When compared to publicly available datasets of glucocorticoid-induced gene expression from an in vitro cell line study and from an in vivo study of patients with ALL, at the level of pathways, expression changes in the 8 hour xenograft samples showed a similar response to patients treated with glucocorticoids. Replicate analysis revealed that at the 8 hour timepoint, a dataset with high signal and differential expression, using data from 3 replicates instead of 4 resulted in excellent recovery scores of > 0.9. However at other timepoints with less signal very poor recovery scores were obtained with 3 replicates.
The NOD/SCID xenograft mouse model provides a reproducible experimental system in which to investigate clinically-relevant mechanisms of drug-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.