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In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

ABSTRACT: We used an in vivo short hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase, Syk. In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation. Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using an Itgb3 knockout mouse model. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. R940406 (R406, the active metabolite of fostamatinib) was supplied by Rigel Pharmaceuticals, Inc., South San Francisco, CA, and AstraZeneca Pharmaceuticals, Wilmington, DE, USA. R406 was resuspended in dimethyl sulfoxide (DMSO) (Sigma-Aldrich) and stored at −80°C. . HL-60, U937 and KG-1 cell lines were purchased from the American Type Culture Collection. MOLM-14 cell lines were provided by Dr. Scott Amstrong (Dana-Farber Cancer Institute, Boston MA, USA.) All cell lines were maintained in RPMI 1640 (Cellgro) supplemented with 1% penicillin-streptomycin and 10% fetal bovine serum (FBS, Sigma-Aldrich) at 37 °C with 5% CO2.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46302 | GEO | 2013/04/24

SECONDARY ACCESSION(S): PRJNA198660

REPOSITORIES: GEO

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In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

Project description:We used an in vivo short hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies.M-BM- In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase, Syk.M-BM- In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation. M-BM- Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using an Itgb3 knockout mouse model.M-BM- Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. R940406 (R406, the active metabolite of fostamatinib) was supplied by Rigel Pharmaceuticals, Inc., South San Francisco, CA, and AstraZeneca Pharmaceuticals, Wilmington, DE, USA. R406 was resuspended in dimethyl sulfoxide (DMSO) (Sigma-Aldrich) and stored at M-bM-^HM-^R80M-BM-0C. . HL-60, U937 and KG-1 cell lines were purchased from the American Type Culture Collection. MOLM-14 cell lines were provided by Dr. Scott Amstrong (Dana-Farber Cancer Institute, Boston MA, USA.) All cell lines were maintained in RPMI 1640 (Cellgro) supplemented with 1% penicillin-streptomycin and 10% fetal bovine serum (FBS, Sigma-Aldrich) at 37 M-BM-0C with 5% CO2. MOLM-14, U937, HL-60 and KG-1 cells were grown in 4mM R406 for 24 hours

2013-04-24 | E-GEOD-46302 | biostudies-arrayexpress

Effect of LXR agonist T0901317 on the intestinal transcriptome in mice.

Project description:Mice were treated for three days by oral gavage with the synthetic LXR ligand T0901317 (Cayman chemical, USA) using a dose of 50 mg/kg/day in vehicle (0.5% Carboxy-methylcellulose; 400 cPs (Sigma-Aldrich, USA); 0.2% Tween80 (Sigma-Aldrich, USA)) or solely the vehicle (control group). Mice were anesthetized with isoflurane and euthanized by cardiac puncture followed by cervical dislocation. Intestines were flushed with ice cold PBS and frozen in liquid nitrogen.

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Targeting the Creatine Kinase Pathway in EVI1-Positive Acute Myeloid Leukemia

Project description:Purpose: Identify new targets in EVI1-Positive Acute Myeloid Leukemia Methods: Treatment with cyclocreatine of EVI1-driven AML cell lines TF-1, UT-7 and UCSD-AML1. Cyclocreatine was purchased from Sigma-Aldrich (Sigma). TF-1, UT-7 and UCSD-AML1 cells were treated in quadruplicate with either vehicle or 3 mM cyclocreatine for 24 hours. Total RNA was extracted and profiled by RNA sequencing (HiSeq, Illumina) at BioMicroCenter from Massachusetts Institute of Technology (Cambridge, MA, USA). Results: Alteration of arginine-creatine metabolism by the small-molecule cyclocreatine selectively decreased the viability, promoted cell cycle arrest and apoptosis of EVI1-positive AML cells. Conclusions: Targeting CKMT1 is a promising therapeutic strategy for the EVI1-driven AML subtype that is highly resistant to current treatment regimens.

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AKT/PACS2 participates in renal vascular hyperpermeability by regulating endothelial fatty acid oxidation in diabetic mice

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2022-08-12 | PXD033227 | Pride

In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

Project description:Primary leukemia stem cells (LSCs) reside in an in vivo microenvironment that supports the growth and survival of malignant cells. We used an in vivo short hairpin RNA (shRNA) screening approach to identify novel genes that are essential for primary murine MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is selectively essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation. In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation in long term transplantation assays. We explored the signaling pathways downstream of Itgb3 using an additional in vivo shRNA screen and identified Syk as a critical mediator of Itgb3 activity in leukemia. Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using the Itgb3 knockout mouse model. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML, and demonstrate the utility of in vivo RNA interference screens. We examined the effect of Itgb3 knockdown by gene expression profiling in primary leukemia cells.

2013-04-24 | E-GEOD-46307 | biostudies-arrayexpress

Transcription profiling by array of human bladder cancer cell lines with or without TP53 mutations

Project description:The established cell lines RT4, 5637 and T24 from human bladder TCC were obtained from the Cell Bank of the Federal University of Rio de Janeiro, Brazil. The 5637 cells harbor two TP53 mutations, at codon 72 (Arg . Pro) and codon 280 (Arg . Thr).T24 cells contain a TP53 allele encoding an in-frame deletion of tyrosine 126. Both cell lines were established from high-grade bladder tumors. No specific mutations were detected in RT4 cells, which had been established from a low-grade papillary bladder tumor. The RT4 and T24 cell lines were maintained in DulbeccoM-^Rs modified EagleM-^Rs medium (Sigma-Aldrich, Inc, St Louis, MO, USA), and the 5637 cells were kept in Roswell Park Memorial Institute medium (Sigma-Aldrich). Both media were supplemented with 10% fetal bovine serum (Cultilab Ltd, Campinas, Brazil), 100 U/mL penicillin G (Sigma-Aldrich), 100 U/mL streptomycin (Sigma-Aldrich) and 1% kanamycin sulfate (Amresco, Branded Products Group, Solon, OH, USA); cells were cultured at 37M-:C in an atmosphere of 5% CO2. A pooled reference design was chosen. More specifically, each array was hybridized with the same reference sample labeled with Cy5, while the experimental samples (control or treated) were labeled with Cy3.

2010-10-30 | E-MEXP-2859 | biostudies-arrayexpress

Expression Profiles of HepG2 cells treated with following compounds: Azathriopine, Furan, Tetradecanoyl phorbol acetate, Tetrachloroethylene, Diazinon and Dmannitol

Project description:The transcriptomic changes induced in the human liver cell line HepG2 by Azathriopine (250µM, Sigma-Aldrich), Furan (2mM, Sigma-Aldrich), Tetradecanoyl phorbol acetate (500nM, Sigma-Aldrich), Tetrachloroethylene (2mM, Sigma-Aldrich), Diazinon (250µM, Sigma-Aldrich) and Dmannitol (250µM, Sigma-Aldrich) during 4, 8, 24, 48 and 72hrs As a solvent control for Azathriopine, Furan, Diazinon and Tetradecanoyl phorbol acetate, DMSO was used (0.5%); As a solvent control for tetrachloroethylene, ethanol was used (0.5%); As a solvent control for D-mannitol, HBSS was used (0.5%)

2015-01-13 | GSE58235 | GEO

In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

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RNA expression profiling in G-CCE cells with a knock down of MMTR or overexpression of the full length, N-terminal or C-terminal of MMTR

Project description:The goal of this study is to compare total RNA expression profiles among wild type, MMTR knock down, and overexpression of full length, C-terminal and N-terminal in G-CCE cells at d0 and d3 after differentiation. All cell lines were maintained in DMEM supplemented with 15% heat-inactivated fetal bovine serum (FBS; Gibco, 16141079), 1X MEM Non-Essential Amino Acids Solution (Sigma-Aldrich, M7145), 300 μM monothioglycerol (Sigma-Aldrich, M6145), 1X penicillin/streptomycin, and 1000 U/ml Leukima inhibitory factor (LIF, Sigma-Aldrich, ESG1107) in 0.1% gelatin coated cell culture dishes. To induce differentiation of G-CCE cell lines, Leukemia inhibitory factor (LIF) was eliminated from the culture media for 3 days. Total RNA was amplified and purified using the Ambion Illumina RNA amplification kit (Ambion, AMIL1791) to yield biotinylated cRNA according to the manufacturer’s instructions. Briefly, 550 ng of total RNA was reverse-transcribed to cDNA using a T7 oligo(dT) primer.750 ng of labeled cRNA samples were hybridized to each Mouse WG-6 expression v.2 bead array for 16-18 h at 58°C, according to the manufacturer's instructions (Illumina). Detection of array signal was carried out using Amersham fluorolink streptavidin-Cy3 (Invitrogen, SA1010) following the bead array manual. Arrays were scanned with an Illumina bead array Reader confocal scanner

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