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The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

ABSTRACT: The NF-κB pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-κB response is regulated by the activation state of the IκB kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-κB is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-κB activation and the potential importance of NF-κB in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo. Transcriptional consequences of NF-kB inactivation in human T-ALL1 cell line

ORGANISM(S): Homo sapiens

PROVIDER: GSE20667 | GEO | 2011/05/07

SECONDARY ACCESSION(S): PRJNA124923

REPOSITORIES: GEO

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The Notch/Hes1 pathway sustains NF-M-NM-:B activation through CYLD repression in T cell leukemia

Project description:The NF-M-NM-:B pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-M-NM-:B response is regulated by the activation state of the IM-NM-:B kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-M-NM-:B is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-M-NM-:B activation and the potential importance of NF-M-NM-:B in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-M-NM-:B activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo. Transcriptional consequences of NF-kB inactivation in human T-ALL1 cell line Twenty samples were analyzed: human T-ALL, CEM, KOPT-K, DND41, HPB-ALL cells lines have been treated at 100uM for 16 hours with control peptide or IKKM-NM-3 Nemo binding domain (NBD) inhibitory peptide, that specifically block the canonical NF-M-NM-:B activity by disrupting the interaction of IKKM-NM-3 to IKKM-NM-2 and IKKM-NM-1

2011-05-07 | E-GEOD-20667 | biostudies-arrayexpress

Homo sapiens

Project description:The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

| PRJNA124923 | ENA

Expression data from Hes1 conditional knock-out NOTCH1-induced leukemias

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

Notch/HES1-mediated PARP1 activation: A cell-type specific mechanism for tumor suppression

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

Expression data from Hes1 conditional knock-out NOTCH1-induced leukemias

2015-05-07 | GSE65863 | GEO

HES1 and HES4 have both unique and overlapping roles as downstream mediators of Notch-dependent hematopoietic lineage decisions in human

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

Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embyronic and induced pluripotent cells

2013-06-01 | GSE47466 | GEO

Targeting the NF-κB signaling pathway in Notch1-induced T cell leukemia

Project description:T cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that the majority of TALL patients carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively-active Notch1 activates the NF-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of multiple well-characterized NF-κB target genes in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-κB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These studies identify NF-κB as one of the major mediators of NOTCH1-induced transformation and suggest that the NF-κB pathway is a potential target of future targeted therapies of T-ALL. Keywords: gene expression analysis, signaling pathway alteration

2006-12-02 | GSE6396 | GEO

Notch/HES1-mediated PARP1 activation: A cell-type specific mechanism for tumor suppression

2011-12-12 | GSE26366 | GEO

Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embyronic and induced pluripotent cells

Project description:Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells (hPSCs) of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and siRNA to Notch receptors we have demonstrated that Notch1, but not Notch2 activation, induced HES1 expression and generation of committed hematopoietic progenitors. Using gain and loss of function approaches, this was shown to be attributed to Notch signaling regulation through HES1, that dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs. endothelial fate specification. Human pluripotent stem cells (hPSCs) have differentiation potential into three embryonic germ layers including blood. Notch signaling is one of important signaling pathways involved in blood differentiation of hPSCs. Thus, in order to examine the effect of Notch signaling pathways during hematopoietic differentiation of hPSCs, embryoid bodies (EBs) were formed and cultured for 10 days in the combination of cytokines and growth factors (Chadwick, Blood, 2003; 300 ng/ml of SCF, 300 ng/ml of Flt-3L, 10 ng/ml of IL-3, 10 ng/ml of IL-6, and 50 ng/ml of G-CSF) to induce differentiation into blood. Additionally, CD31+CD45- bipotent hemogenic precursors were isolated from day10 hematopoietic EBs (Wang et al., Immunity, 2004)

2013-06-01 | E-GEOD-47466 | biostudies-arrayexpress

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