Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA642171 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors from the vast amount of tumor descriptive expression data. We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap. With this technique at hand, we analyzed the role of the transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced azacitidine-induced cell death, suggesting that azacitidine can regulate KLF4 re-expression. These results support the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4. Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.
2020-06-27 | GSE153382 | GEO
Project description:Background:Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors, from the vast amount of tumor descriptive expression data. Methods:We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap. Results:With this technique at hand, we analyzed the role of the transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced azacitidine-induced cell death, suggesting that azacitidine can regulate KLF4 re-expression. These results support the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4. Conclusion:Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.
| S-EPMC7493381 | biostudies-literature
Project description:We investigated the gene expression changes in a library of meso PDX models.
2022-06-17 | E-MTAB-11783 | biostudies-arrayexpress
Project description:We investigated the gene expression changes in a library of small cell lung carcinoma (SCLC) patient-derived xenograft (PDX) models.
2022-02-07 | E-MTAB-11230 | biostudies-arrayexpress
Project description:Histone profile for wild type MEF and secondary MEF with Dox-inducible vectors for Klf4, Sox2 and Oct4 (KSO).
2010-12-31 | GSE21271 | GEO
Project description:Better understanding alveolarization mechanisms could help improving prevention and treatment of diseases characterized by reduced alveolar number, especially bronchopulmonary dysplasia (BPD). Although signaling through fibroblast growth factor (FGF) receptors is essential for alveolarization, involved ligands are unidentified. FGF18 whose expression peaks during alveolar septation is likely to be involved. Herein, a mouse model of inducible, lung-targeted FGF18-transgene was used to advance the onset of FGF18 expression, and genome-wide expression changes were determined. keywords: transgenic mice, alveolarization, angiogenesis, fibrosis, epithelial-mesenchymal transition.
2011-07-06 | GSE22283 | GEO
Project description:Histone profile for wild type MEF and secondary MEF with Dox-inducible vectors for Klf4, Sox2 and Oct4 (KSO). ChIP-Seq data for H3K4me3, H3K27me3 and H3K9me3
2010-12-31 | E-GEOD-21271 | biostudies-arrayexpress
Project description:Better understanding alveolarization mechanisms could help improving prevention and treatment of diseases characterized by reduced alveolar number, especially bronchopulmonary dysplasia (BPD). Although signaling through fibroblast growth factor (FGF) receptors is essential for alveolarization, involved ligands are unidentified. FGF18 whose expression peaks during alveolar septation is likely to be involved. Herein, a mouse model of inducible, lung-targeted FGF18-transgene was used to advance the onset of FGF18 expression, and genome-wide expression changes were determined. keywords: transgenic mice, alveolarization, angiogenesis, fibrosis, epithelial-mesenchymal transition. Four pairs of simple and double transgenic pups issued from 4 different litters were selected on the basis of FGF18 transgene induction. RNA from the mice lung were extracted and hybridized on Affymetrix microarrays.
2011-07-05 | E-GEOD-22283 | biostudies-arrayexpress
Project description:A stably transfected inducible system for KLF4 was established in RKO cells as previously described (Chen et al., 2001; Chen et al., 2003). This cell line, called EcR-RKO/KLF4, contains stably transfected receptors for the insect hormone, ecdysone (EcR), and a full-length mouse KLF4 cDNA driven by a promoter that responds to ecdysone and its analogue, ponasterone A. Cells were treated with 5 µM ponasterone A (PA), for various time durations. To control for the experiment, the vehicle, ethanol, was added for the same periods of time. Keywords: Time course
2005-08-13 | GSE3113 | GEO
Project description:Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by the introduction of the transcription factors Oct4, Sox2, Klf4 and cMyc using various methods. Here, we describe a new approach for the derivation of murine iPSCs using a polycistronic non-viral inducible vector integrated into pseudo attP sites via the C31 integrase-mediated site-specific recombination and subsequent vector excision by Cre recombinase. The pluripotency of the derived iPSCs was proved by in vitro and in vivo tests. The derived transgene-free iPSCs reactivated the endogenous pluripotency genes like e.g. Oct4, Sox2 and Nanog and the global gene expression profiles of iPSCs lines are highly similar to ESCs and distinct from parental murine fibroblasts. We demonstrated the differentiation potential of iPSCs by generation cells of the three germ layers as well as we successfully created germline chimeric mice from transgene-free iPSCs. In this study, we presented an efficient method for the generation of transgene-free iPSCs using dual-recombinase technology.
2014-03-29 | GSE51605 | GEO