Unknown,Transcriptomics,Genomics,Proteomics

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A Pre-clinical model of induction therapy and relapse in pediatric acute lymphoblastic leukemia

ABSTRACT: Relapse and acquired drug resistance in T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem. The current study used a pre-clinical model of induction therapy for pediatric ALL in NOD/SCID mice (Samuels et al Blood Cancer Journal (2014) 4, e232; doi:10.1038/bcj.2014.52) to study the development of drug resistance. We performed transcription profiling by array of human CD45-positive lymphocytes from patients with acute pediatric lymphoblastic leukemia, xenografted in NOD/SCID mice treated with vincristine, daunorubicin, dexamethasone and L-asparagine. Both the primary-patient-derived and xenograft cells were analysed. The VLXD2 treatment regime is described in full in the protocols associated with this submission and in Samuels et al (Blood Cancer Journal (2014) 4, e232; doi:10.1038/bcj.2014.52). This study is an extension of E-MEXP-3916.

INSTRUMENT(S): GeneChip Scanner 3000 7G

ORGANISM(S): Homo sapiens

SUBMITTER: Julia Wells

PROVIDER: E-MTAB-4759 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Glucocorticoids are critical components of combination chemotherapy regimens in pediatric acute lymphoblastic leukemia (ALL). The pro-apoptotic BIM protein is an important mediator of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, while the anti-apoptotic BCL2 confers resistance. The signaling pathways regulating BIM and BCL2 expression in glucocorticoid-treated lymphoid cells remain unclear. In this study, pediatric ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids were exposed to dexamethasone in vivo. In order to understand the basis for differential in vivo glucocorticoid sensitivity of PDXs, microarray analysis of gene expression was carried out on 5 each of dexamethasone-sensitive and resistant PDXs . This provided a global understanding of dexamethasone-induced signaling cascades in ALL cells in vivo, and especialy identified the genes that are involved in transducing the apoptotic signal, upstream of BIM/BCL2 dynamic interactions. ALL xenograft cells were inoculated by tail-vein injection into NOD/SCID mice, and engraftment was monitored weekly. When >70% %huCD45+ engraftment in the peripheral blood was apparent, which occurred 8-10 weeks post-transplantation, mice were treated with either dexamethasone (15 mg/kg) or vehicle control by intra-peritoneal (IP) injection, and culled at 8 hours following the treatment. Cell suspensions of spleens were prepared and mononuclear cells enriched to >97% human by density gradient centrifugation. RNA was extracted using the RNeasy Mini Kit (QIAGEN, Valencia, CA, USA), and RNA samples with integrity number (RIN) > 8.0 were amplified and hybridized onto Illumina HumanWG-6 v3 Expression BeadChips (6 samples/chip). All chips (with associated reagents) were purchased from Illumina, and scanned on the Illumina BeadArray Reader according to the manufacturer’s instructions. Microarray data were analyzed using the online modules in GenePattern. 10 xenografts were derived from patients of 5 dexamethasone-good responder and 5 dexamethasone-poor responder. Each xenograft was innoculated into 5-6 mice, and treated with dexamethasone (15 mg/kg) or vehicle control. In total spleen-harvest xenograft samples from 58 mice were analyzed using microarray.

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A Pre-clinical model of induction therapy and relapse in pediatric acute lymphoblastic leukemia

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