Growth factor independence 1 (Gfi1) as a new target for leukemia therapy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Lothar Vassen
PROVIDER: E-GEOD-32910 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Using (conditional) Gfi1 knock-out mice we show that ablation of the transcriptional repressor Gfi1 cures mice from lymphoid leukemia and reduces the expansion of primary human T-ALL xenografts in mice. We find that Gfi1 alters the p53 dependent transcriptional activation of a substantial subset of known p53 target genes and thus sets a threshold for cell death. We used Affymetrix mouse Gene-1.0-ST arrays to define the changes in the gene expression pattern of wt or Gfi1-KO thymocytes (Gfi1-fl/fl X MX-CRE, induced by pIpC) that were either untreated (WT, GfiKO thymocytes), irradiated (WT_irr, Gfi1KO_irr), ENU transformed (WT_Tum, Gfi1KO_Tum), or transformed by Notch1-CT and ENU-induced to enhance tumorigenesis (WT_Notch_Tum, Gfi1KO_Notch_Tum).
2012-10-03 | GSE32910 | GEO
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2011-07-27 | E-GEOD-23341 | biostudies-arrayexpress
Project description:Using Gfi1b conditional mice, deletion of gfi1b in the hematopietic system was induced by injecting MxCre tg Gfi1bfl/fl mice with pIpC. 30 days after injection, Cd150 pos, Cd 48 neg, Lin neg Sca and c-kit pos stem cells were sortrted from Gfi1bfl/fl and Mxcre tg Gfi1bfl/fl mice and analysed. We used the mouse Affymetrix Gene ST Array. The study should determine whether loss of Gfi1 alters the gene expression pattern in the hematopietic stem cells.
2010-09-03 | E-GEOD-20655 | biostudies-arrayexpress
Project description:Thymocytes from mice transplanted with bone marrow cells infected with retrivirus for ERG were compared with control thymocytes regarding to gene expression. Mutations in Notch1 gene were not detected in the thymocytes.
2011-04-16 | E-MEXP-2988 | biostudies-arrayexpress
Project description:Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a common integration site in Moloney-murine-leukemia-virus-induced T-cell leukemia. Gfi1-/- mice display increased apoptosis of developing thymocytes and T lymphopenia; however, there are contradictory reports of the absolute number of Gfi1-/- early T lineage progenitors. We used floxed alleles of Gfi1 crossed to various T-cell-specific Cre transgenes to map the requirements for Gfi1 during lymphoid priming and development. We show that Gfi1 is necessary for the proper formation and function of both lymphoid-primed multipotent progenitors and early T lineage progenitors. These defects correlate with a global inability of Gfi1-/- progenitors to enforce the activation of lymphoid genes including IL7R, Rag1, Flt3 and Notch1. Forced expression of intracellular Notch1 fails to rescue the Gfi1-/- defective lymphoid gene signature or Gfi1-/- T cell development. Instead, activation of Notch1 in Gfi1-/- cells results in a potent synthetic lethal phenotype that is most dramatic in immature thymocytes, but absent in mature peripheral T cells where developmental transcriptional programs are silent. Moreover, we find that the requirement for Gfi1-transcriptional integration of Notch-driven lymphoid transcriptional programs is cell autonomous. Our data indicate that Gfi1 is required at multiple independent stages of lymphoid development. In hematopoietic progenitors Gfi1 is necessary to integrate Notch1 signaling, mediate lymphoid priming, the formation of early T lineage progenitors and subsequent T lineage commitment. Lineage negative cells were purified by magnetic beads from RosaCreERT2 Gfi1 ex4-5 floxed mice and an activated Notch1 signal was introduced using a GFP+ retroviral vector. GFP+ progenitors were FACS-sorted and cultured in semi-solid media for one week to allow sufficient time to to instruct lymphoid differentiation, then replated in 1uM 4-OHT or EtOH control. After an additional 7 days, CFU were disrupted and RNA was isolated for global gene expression using microarrays.
2014-10-01 | E-GEOD-41162 | biostudies-arrayexpress
Project description:Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a common integration site in Moloney-murine-leukemia-virus-induced T-cell leukemia. Gfi1-/- mice display increased apoptosis of developing thymocytes and T lymphopenia; however, there are contradictory reports of the absolute number of Gfi1-/- early T lineage progenitors. We used floxed alleles of Gfi1 crossed to various T-cell-specific Cre transgenes to map the requirements for Gfi1 during lymphoid priming and development. We show that Gfi1 is necessary for the proper formation and function of both lymphoid-primed multipotent progenitors and early T lineage progenitors. These defects correlate with a global inability of Gfi1-/- progenitors to enforce the activation of lymphoid genes including IL7R, Rag1, Flt3 and Notch1. Forced expression of intracellular Notch1 fails to rescue the Gfi1-/- defective lymphoid gene signature or Gfi1-/- T cell development. Instead, activation of Notch1 in Gfi1-/- cells results in a potent synthetic lethal phenotype that is most dramatic in immature thymocytes, but absent in mature peripheral T cells where developmental transcriptional programs are silent. Moreover, we find that the requirement for Gfi1-transcriptional integration of Notch-driven lymphoid transcriptional programs is cell autonomous. Our data indicate that Gfi1 is required at multiple independent stages of lymphoid development. In hematopoietic progenitors Gfi1 is necessary to integrate Notch1 signaling, mediate lymphoid priming, the formation of early T lineage progenitors and subsequent T lineage commitment.
2014-10-01 | GSE41162 | GEO
Project description:Double-positive (DP) thymocytes respond to intrathymic TCR signals by undergoing positive selection and lineage differentiation into single-positive (SP) mature cells. Concomitant with these wellcharacterized events is the acquisition of a mature T cell gene expression program characterized by the induction of effector molecules IL-7Ra, S1P1 and CCR7, but the underlying mechanism remains elusive. We report here that transcription repressor Gfi1 orchestrates the fidelity of DP gene expression program and developmental maturation into SP cells. Loss of Gfi1 resulted in premature induction of effector genes and transcription factors Foxo1 and Klf2 in DP thymocytes, and accumulation of post-selection intermediate populations and accelerated transition into SP cells. Strikingly, partial loss of Foxo1 function, but not restored survival fitness, rectified the dysregulated gene expression and thymocyte maturation in Gfi1-deficient mice. Our results establish Gfi1-Foxo1 axis and the transcriptional circuitry that actively maintain DP identity and shape the proper generation of mature T cells
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Project description:Investigation of whole genome gene expression level changes in Mus musculus 3B4.15 T hybridoma cells treated with 1microMolar Dexamethasone compared to mock treated cells. Interleukin-7 receptor alpha (IL-7Rα) is essential for T cell survival and differentiation. Glucocorticoids are potent enhancers of IL-7Rα expression with diverse roles in T cell biology. Here we identify the transcriptional repressor, Growth factor independent-1 (Gfi1), as a novel intermediary in glucocorticoid-induced IL-7Rα upregulation. We found Gfi1 to be a major inhibitory target of dexamethasone by microarray expression profiling of 3B4.15 T-hybridoma cells. Concordantly, retroviral transduction of Gfi1 significantly blunted IL-7Rα upregulation by dexamethasone. To further assess the role of Gfi1 in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. By introducing this BAC reporter transgene into either Gfi1-deficient or Gfi1-transgenic mice, we document in vivo that IL-7Rα transcription is upregulated in the absence of Gfi1 and downregulated when Gfi1 is overexpressed. Strikingly, the in vivo regulatory role of Gfi1 was specific for CD8+, and not CD4+ T cells or immature thymocytes. These results identify Gfi1 as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo. A six chip study using total RNA recovered from three separate flasks of mock treated 3B4.15 cells and three separate flasks of Dexamethasone treated 3B4.15 cells . Each chip measures the expression level of 44170 target genes
2012-07-12 | E-GEOD-39296 | biostudies-arrayexpress
Project description:Investigation of whole genome gene expression level changes in Mus musculus 3B4.15 T hybridoma cells treated with 1microMolar Dexamethasone compared to mock treated cells. Interleukin-7 receptor alpha (IL-7Rα) is essential for T cell survival and differentiation. Glucocorticoids are potent enhancers of IL-7Rα expression with diverse roles in T cell biology. Here we identify the transcriptional repressor, Growth factor independent-1 (Gfi1), as a novel intermediary in glucocorticoid-induced IL-7Rα upregulation. We found Gfi1 to be a major inhibitory target of dexamethasone by microarray expression profiling of 3B4.15 T-hybridoma cells. Concordantly, retroviral transduction of Gfi1 significantly blunted IL-7Rα upregulation by dexamethasone. To further assess the role of Gfi1 in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. By introducing this BAC reporter transgene into either Gfi1-deficient or Gfi1-transgenic mice, we document in vivo that IL-7Rα transcription is upregulated in the absence of Gfi1 and downregulated when Gfi1 is overexpressed. Strikingly, the in vivo regulatory role of Gfi1 was specific for CD8+, and not CD4+ T cells or immature thymocytes. These results identify Gfi1 as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo.
2012-07-13 | GSE39296 | GEO
Project description:T cell-specific transgenic expression of microRNA-181d reduced number of immature CD4+CD8+ thymocytes. Microarray analysis was performed to reveal differentially expressed genes between the wild type and microRNA-181d transgenic thymocytes. Whole thymus tissues were isolated from the wild type (C57BL/6) and microRNA-181d transgenic mice (Tg-38 line), followed by total RNA isolation.
2014-01-21 | E-GEOD-51778 | biostudies-arrayexpress