Comment[ArrayExpressAccession]	E-GEOD-75615
MAGE-TAB Version	1.1		
Public Release Date	2016-01-17
Investigation Title	Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1		
Comment[Submitted Name]	Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1
Experiment Description	Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GAB2 as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transduced Gab2-/- bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors PI3K or SHP2. GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph+ hematologic neoplasms. RNA-Seq expression profiling of 6 mouse bone marrow samples: 3 GAB2 WT (+/+) and 3 GAB2 NULL (-/-)		
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	Neel	Sayad	Gu
Person First Name	Benjamin	Azin	Shengqing
Person Mid Initials	G.		
Person Email	benjamin.neel@nyumc.org		
Person Affiliation	NYU Perlmutter Cancer Centre		
Person Address	NYU Perlmutter Cancer Centre, 550 First Avenue, New York, New York, USA		
Person Roles	submitter		
Protocol Name	P-GSE75615-2	P-GSE75615-1	
Protocol Description	Genomic alignment was performed with Bowtie, using default parameters. Gene expression levels were estimated and compared using Cufflinks. Genome_build: mm10 (GRCm38) Supplementary_files_format_and_content: FPKM	RNA (150 ng) from each sample was reverse transcribed into cDNA by using the Illumina TruSeq Stranded mRNA kit. cDNA libraries were size-indexed and validated using an Agilent Bioanalyzer, and their concentrations confirmed by qPCR. Six different libraries (3 WT-Gab2+/+ and 3 Gab2-/-) were normalized to 10 nM and pooled. Pooled libraries (8 pmol each) were loaded onto Illumina cBot for cluster generation, and the flow cell was subjected to 100 cycles of paired-end sequencing on an Illumina HiSeq 2000.	
Protocol Type	normalization data transformation protocol	nucleic acid library construction protocol	
Comment[SecondaryAccession]	GSE75615		
Comment[GEOReleaseDate]	2016-01-17		
Comment[ArrayExpressSubmissionDate]	2015-12-02		
Comment[GEOLastUpdateDate]	2016-01-19		
Comment[AEExperimentType]	RNA-seq of coding RNA		
Comment[AdditionalFile:Data1]	GSE75615_ALL_FPKM.txt		
Comment[SecondaryAccession]	SRP066909		
Comment[SequenceDataURI]	http://www.ebi.ac.uk/ena/data/view/SRR2969530-SRR2969535		
SDRF File	E-GEOD-75615.sdrf.txt