Expression data from Hes1 conditional knock-out NOTCH1-induced leukemias
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE65863 | GEO | 2015/05/07
SECONDARY ACCESSION(S): PRJNA275244
REPOSITORIES: GEO
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Project description:To formally address the biological activity of Hes1 in vivo, we tested the interaction between oncogenic NOTCH1 and acute Hes1 loss in a retroviral-transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later. We performed microarray gene expression analysis of Hes1 wild type and Hes1-/- NOTCH1 induced leukemias
2015-05-07 | E-GEOD-65863 | biostudies-arrayexpress
Project description:To formally address the tumor suppressor activity of Sh2b3 in vivo, we tested the interaction between oncogenic NOTCH1 and Sh2b3 loss in a retroviral- transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later.
2013-11-06 | GSE44025 | GEO
Project description:To formally address the tumor suppressor activity of Sh2b3 in vivo, we tested the interaction between oncogenic NOTCH1 and Sh2b3 loss in a retroviral- transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later. We performed microarray gene expression analysis of Sh2b3 wild type and Sh2b3–/– NOTCH1 induced leukemias
2013-11-06 | E-GEOD-44025 | biostudies-arrayexpress
Project description:In both mouse and human, Notch1 activation is the main initial driver to induce T-cell development in hematopoietic progenitor cells. The initiation of this developmental process coincides with Notch1-dependent repression of differentiation towards other hematopoietic lineages. Although well described in mice, the role of the individual Notch1 target genes during these hematopoietic developmental choices is still unclear in human. Here, we investigated the functional capacity of the Notch1 target genes HES1 and HES4 to modulate human Notch1-dependent hematopoietic lineage decisions. Using well-established in vitro cocultures and RNA sequencing, we show that HES1 acts as a repressor of differentiation by maintaining a quiescent stem cell signature in CD34+ hematopoietic progenitor cells. While HES4 can also inhibit NK and myeloid development like HES1, it acts differently on the T- versus B-cell lineage choice. Surprisingly, HES4 is not capable of repressing B-cell development, the most sensitive hematopoietic lineage with respect to Notch-mediated repression. In contrast to HES1, HES4 promotes initiation of early T-cell development. Overall, we show that the Notch1 target genes HES1 and HES4 display both unique and overlapping functions downstream of Notch during human hematopoietic lineage decisions.
2020-07-27 | GSE130614 | GEO
Project description:Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-seq analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR) (asialoglycoprotein receptor 1, ASGR1) physically associates with Notch1 and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Dll4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.
2024-04-12 | GSE250529 | GEO
Project description:To formally address the biological activity of HES1 in vitro, we measured the transcriptional effect of HES1 inactivation infectiing CUTLL1 leukemia cell lines with shHES1 HES1 knockdown triggered apoptosis in human T-ALL lymphoblasts. We show that HES1 inactivation induces programmed cell death in leukemia lymphoblasts
2015-05-07 | GSE65872 | GEO
Project description:Notch signaling plays both oncogenic and tumor suppressor roles, depending on cell type. In contrast to T cell acute lymphoblastic leukemia (T-ALL), where Notch activation promotes leukemogenesis, induction of Notch signaling in B-ALL leads to growth arrest and apoptosis. The Notch target Hairy/Enhancer of Split1 (HES1) is sufficient to reproduce this tumor suppressor phenotype in B-ALL, however the mechanism is not yet known. Here we report that HES1 regulates pro-apoptotic signals via the novel interacting protein Poly ADP-Ribose Polymerase1 (PARP1) in a cell type-specific manner. The interaction of HES1 with PARP1 inhibits HES1 function, induces PARP1 activation and results in PARP1 cleavage in B-ALL. HES1-induced PARP1 activation leads to self-ADP ribosylation of PARP1, consumption of NAD+, diminished ATP levels, and translocation of the Apoptosis Inducing Factor (AIF) from mitochondria to the nucleus, resulting in apoptosis in B-ALL, but not T-ALL. Importantly, induction of Notch signaling via the Notch agonist peptide DSL can reproduce these events and leads to BALL apoptosis. The novel interaction of HES1 and PARP1 in B-ALL modulates the function of the HES1 transcriptional complex and signals through PARP1 to induce apoptosis. This mechanism reveals a cell type-specific pro-apoptotic pathway which may lead to Notch agonist-based cancer therapeutics. Study involved the gene expression profiling of human acute lymphoblastic leukemia samples, and comparison of the levels of expression NOTCH1 pathway genes and targets across ALL subtypes
2011-12-12 | E-GEOD-26366 | 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:To formally address the biological activity of HES1 in vitro, we measured the transcriptional effect of HES1 inactivation infectiing CUTLL1 leukemia cell lines with shHES1 HES1 knockdown triggered apoptosis in human T-ALL lymphoblasts. We show that HES1 inactivation induces programmed cell death in leukemia lymphoblasts We performed microarray gene expression analysis of shHES1 vs shRNA LUC
2015-05-07 | E-GEOD-65872 | biostudies-arrayexpress
Project description:Hes1 regulates hair follicle regenerative cycling We used microarrays to profile the global gene expression of hair follicle stem cells in the telogen phase at P70 after depilation at P49. These microarray analysis were designed to identify the signaling networks regualting hair follicle stem cell behavior in the presence or absence of Hes1.
2019-12-31 | GSE101892 | GEO