Investigation Title	Transcription profiling of human T-ALL samples to investigate synergistic interaction of gamma-secretase inhibitor therapy and glucocorticoids	
Comment[Submitted Name]	Synergistic interaction of gamma-secretase inhibitor therapy and glucocorticoids in T-ALL	
Experimental Design	unknown_experiment_design_type	transcription profiling by array	
Experimental Design Term Source REF		EFO	
Comment[AEMIAMESCORE]	3	
Comment[SecondaryAccession]	GSE7067	
Comment[ArrayExpressReleaseDate]	2009-01-13	
Comment[ArrayExpressAccession]	E-GEOD-7067	
Comment[MAGETAB TimeStamp_Version]	2010-08-07 16:51:31 Last Changed Rev: 13058	
Experimental Factor Name	
Experimental Factor Type	
Experimental Factor Term Source REF	
Person Last Name	Ferrando	
Person First Name	Adolfo	
Person Mid Initials	A.	
Person Email	af2196@columbia.edu	
Person Phone	
Person Fax	
Person Address	Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave Irving Cancer Research Center 5-505A, New York, 10032, USA	
Person Affiliation	Columbia University	
Person Roles	submitter	
Person Roles Term Source REF		
Quality Control Type	
Quality Control Term Source REF	
Replicate Type	
Replicate Term Source REF	
Normalization Type	
Normalization Term Source REF	
Date of Experiment	
Public Release Date	2009-01-13	
PubMed ID	
Publication DOI	
Publication Author List	
Publication Title	
Publication Status	
Publication Status Term Source REF	
Experiment Description	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. Experiment 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.	
Protocol Name	P-G7067-1	P-G7067-6	P-G7067-7	P-G7067-2	P-G7067-5	P-G7067-4	P-G7067-3	P-AFFY-6	Affymetrix:Protocol:ExpressionStat	
Protocol Type	grow	specified_biomaterial_action	specified_biomaterial_action	specified_biomaterial_action	specified_biomaterial_action	nucleic_acid_extraction	labeling	feature_extraction	bioassay_data_transformation	
Protocol Description	RPMI 20% FBS Pen/Strep, 37C, 5%CO2	Glucocorticoid (Dexamethasone 1 microM) treatment for 24 hours	Glucocorticoid (Dexamethasone 1 microM) plus gamma-secretase inhibitor (CompE 100 nM) treatment for 24 hours	Vehicle only(DMSO) treatment	Gamma-secretase inhibitor (CompE 100nM) treatment for 24 hours	RNAqueous RNA extraction kit (Ambion)	Standard Affymetix protocol	Title: Affymetrix CEL analysis. Description: 	Title: Affymetrix CHP Analysis (ExpressionStat). Description: 	
Protocol Parameters	
Protocol Hardware	
Protocol Software								MicroArraySuite 5.0	MicroArraySuite 5.0	
Protocol Contact	
Protocol Term Source REF	
SDRF File	E-GEOD-7067.sdrf.txt	
Term Source Name	ncbitax		The MGED Ontology	ArrayExpress	EFO	
Term Source File	http://www.ncbi.nlm.nih.gov/Taxonomy/taxonomyhome.html		http://mged.sourceforge.net/ontologies/MGEDontology.php	http://www.ebi.ac.uk/arrayexpress	http://www.ebi.ac.uk/efo/	
Term Source Version