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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE6396 | GEO | 2006/12/02

SECONDARY ACCESSION(S): PRJNA99707

REPOSITORIES: GEO

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

Project description: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

2011-05-07 | GSE20667 | GEO

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2020-08-06 | PXD018743 | Pride

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

Expression of ZAP70 in CLL activates NF-κB signalling

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2013-10-22 | GSE51286 | GEO

CDK12 mediated transcriptional regulation in U2OS cells

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2018-07-31 | GSE113926 | GEO

Alpha-kinase 1 functions upstream of IKKs to regulate NF-κB activation in Helicobacter infection

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2019-09-02 | GSE89613 | GEO

Ancestral function of Inhibitors-of-kappaB regulates Caenorhabditis elegans development (RNA-Seq)

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2020-09-01 | GSE146654 | GEO

Ancestral function of Inhibitors-of-kappaB regulates Caenorhabditis elegans development (ChIP-Seq)

2020-09-01 | GSE146652 | GEO

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2019-03-27 | MODEL1809230001 | BioModels

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Project description:T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular calcium (Ca2+) to activate the key transcription factors NFAT and NF-κB. The mechanism of NFAT activation by Ca2+ has been determined; however, the role of Ca2+ in controlling NF-κB signaling is poorly understood and the source of Ca2+ required for NF-κB activation is unknown. We demonstrate that TCR- but not TNF- induced NF-κB signaling upstream of IκB kinase (IKK) activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent CRAC/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-κB protein p65 on Ser536 and that this post- translational modification controls its nuclear localization and transcriptional activation. Notably our data reveal that this role for Ca2+ is entirely separate from its upstream control of IκBα degradation, thereby identifying a novel Ca2+- dependent distal step in TCR-induced NF-κB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKCk-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR induced NF-kB activation and we define a new distal Ca2+-dependent checkpoint in TCR-induced NF-kB signaling that has broad implications for the control of immune cell development and T cell functional specificity.

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