Comment[ArrayExpressAccession]	E-GEOD-56345
MAGE-TAB Version	1.1					
Public Release Date	2014-03-29
Investigation Title	Therapeutic potential of spleen tyrosine kinase inhibition for treatment of high-risk precursor B-cell acute lymphoblastic leukemia					
Comment[Submitted Name]	Therapeutic potential of spleen tyrosine kinase inhibition for treatment of high-risk precursor B-cell acute lymphoblastic leukemia
Experiment Description	This study revealed pathogenic role of pre-BCR-independent SYK activation in high-risk B-ALL. Intensified and central nervous system (CNS)-directed chemotherapy has significantly improved outcomes for pediatric B-acute lymphoblastic leukemia (B-ALL), but confers significant late-effect morbidities. Moreover, many patients suffer relapses, underscoring the need to develop novel, molecularly targeted B-ALL therapies. Using a mouse model, we showed that leukemic B-cells require pre-B-cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo. In diagnostic samples from human B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated growth of 69 B-ALL samples, including high-risk (HR) subtypes. Orally administered fostamatinib significantly reduced high disease burden after xenotransplantation of HR B-ALL samples into immune-deficient mice, and decreased leukemia dissemination into spleen, liver, kidneys and the CNS of recipients. Thus, SYK activation sustains growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL. B-cell leukemia samples (3) from a mutant mouse model were compared to sorted or cultured preB or proB cells from normal mice using Affymetrix GeneChip arrays.					
Term Source Name	ArrayExpress	EFO
Term Source File	http://www.ebi.ac.uk/arrayexpress/	http://www.ebi.ac.uk/efo/efo.owl				
Person Last Name	Kowalski	Danska	Kowalski			
Person First Name	Paul	Jayne	Paul			
Person Mid Initials		S	E			
Person Email	geo@ncbi.nlm.nih.gov					
Person Affiliation	The Hospital for Sick Children					
Person Address	Genetics and Genome Biology, The Hospital for Sick Children, PGCRL - 686 Bay St, Toronto, Ontario, Canada					
Person Roles	submitter					
Protocol Name	P-GSE56345-1	P-GSE56345-4	P-GSE56345-5	P-GSE56345-2	P-GSE56345-3	P-GSE56345-6
Protocol Description	Scaling target signal was 150, used GCOS and MAS5.0 scaling for normalization. ID_REF =  VALUE = MAS5.0 signal intensity ABS_CALL = indicating whether the transcript was present (P), absent (A), or marginal (M) DETECTION P-VALUE = p-value that indicates the significance level of the detection call	cRNA was generated and labelled with biotin using the standard Affymetrix protocols, and hybridized to the Affymetrix Mouse Genome 430 2.0 array.	Hyb/wash was EukGE-WS2V4 protocol, using Affymetrix automated fluidics station, TCAG, Sick Kids.	Cells were isolated ex vivo from murine lymph nodes or cultured in vitro.	Cells were isolated from murine lymph nodes with mechanical and protease disruption to generate a single cell suspension for flow sorting. After sorting, cells were lysed in TRIzol and RNA was extracted. Leukemic cell samples were a minimum of 85% CD19 positive by flow cytometry.	Arrays scanned on Affymetrix GeneChip Scanner 3000 by TCAG, Sick Kids.
Protocol Type	normalization data transformation protocol	labelling protocol	hybridization protocol	growth protocol	nucleic acid extraction protocol	array scanning protocol
Experimental Factor Name	CELL TYPE	STRAIN/BACKGROUND	GENOTYPE			
Experimental Factor Type	cell type	strain/background	genotype			
Comment[SecondaryAccession]	GSE56345					
Comment[GEOReleaseDate]	2014-03-29					
Comment[ArrayExpressSubmissionDate]	2014-03-28					
Comment[GEOLastUpdateDate]	2014-03-31					
Comment[AEExperimentType]	transcription profiling by array					
SDRF File	E-GEOD-56345.sdrf.txt