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Series GSE7067 Query DataSets for GSE7067
Status Public on Dec 01, 2008
Title Synergistic interaction of gamma-secretase inhibitor therapy and glucocorticoids in T-ALL
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL.
Keywords: Drug response
Overall design Duplicate samples (biologic replicas) from CUTLL1 cells were treated for 24 hours with vehicle only (DMSO), dexamethasone (1microM), a gamma-secretase inhibitor (CompE 100nM) and a combination of dexamethasome plus gamma secretase inhibitor at the same concentrations indicated before. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (CompE) or the combination of both treatments.
Contributor(s) Real PJ, Ferrando AA
Citation(s) 19098907
Submission date Feb 19, 2007
Last update date Dec 06, 2018
Contact name Adolfo A Ferrando
Phone 212-851-4611
Organization name Columbia University
Department Institute for Cancer Genetics
Street address 1130 St Nicholas Ave Irving Cancer Research Center 5-505A
City New York
State/province NY
ZIP/Postal code 10032
Country USA
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (8)
GSM169412 CUTLL1_Control_1
GSM169413 CUTLL1_Control_2
GSM169414 CUTLL1_CompE_1
BioProject PRJNA98469

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE7067_RAW.tar 18.6 Mb (http)(custom) TAR (of CEL, CHP)
Processed data provided as supplementary file

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