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Coactivation of NF-kB and Notch signaling is sufficient to induce B cell transformation and enables B-myeloid conversion

ABSTRACT: Coactivation of NF-kB and Notch signaling is sufficient to induce B cell transformation and enables B-myeloid conversion

PROVIDER: PRJNA562513 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10045476_1.fastq.gz	Fastqsanger.gz
	SRR10045476_2.fastq.gz	Fastqsanger.gz
	SRR10045477_1.fastq.gz	Fastqsanger.gz
	SRR10045477_2.fastq.gz	Fastqsanger.gz

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Coactivation of NF-kB and Notch signaling is sufficient to induce B cell transformation and enables B-myeloid conversion

Project description:Comparison of chromatin accessibility between NF-kB and Notch coactivated marginal zone precursor (MZP) B cells and converted myeloid cells from these B cells

2020-08-01 | GSE136408 | GEO

Concurrent activation of NF-kB and Notch signaling is sufficient to induce B cell transformation and enables B-myeloid conversion

Project description:Comparison of transcriptome between control, NF-kB, Notch and NF-kB singly- and doubly-activated spleen marginal zone or precursor B cells, and transformed doubly-activated lymphoma cells

2021-07-11 | GSE116960 | GEO

Concurrent activation of NF-kB and Notch signaling is sufficient to induce B cell transformation and enables B-myeloid conversion

Project description:Concurrent activation of NF-kB and Notch signaling is sufficient to induce B cell transformation and enables B-myeloid conversion

| PRJNA480696 | ENA

Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion.

Project description:NF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.

| S-EPMC6952829 | biostudies-literature

Notch-dependent functional conversion of RUNX factors regulates the initiation of T-lineage program

Project description:Runt-related transcription (RUNX) factors play a key role in T cell development. At the T-lineage commitment checkpoint, RUNX1 undergoes dynamic partner switching, resulting in its redeployment. Here, we investigated the functional differences in RUNX factors between the lymphoid progenitor (LP)- and Notch-stimulated earliest T progenitor stages (Phase 1). We identified CCCTC-binding factor (CTCF) as an LP-specific RUNX1-interacting partner, with LP-specific RUNX1 binding genomic sites significantly enriched for CTCF consensus motifs and co-occupied by CTCF. On Notch stimulation, Notch1 intracellular domain (Notch1-IC) directly interacts with RUNX1 and recruits the RUNX1/Mediator/p300 transcriptional activation complex to Notch-regulated T-signature gene loci. CRISPR/Cas9-mediated stage-specific deletion of RUNX factors and their binding partners revealed that the RUNX1/CTCF complex in LP negatively regulates T-signature gene expression, whereas the RUNX1/Mediator/p300 complex in Phase 1 promotes it. Our findings highlight the crucial role of Notch-mediated functional conversion of RUNX factors, including protein complex re-organization and genomic redeployment in initiating T-lineage program.

2025-05-07 | GSE296265 | GEO

Transcriptional landscapes underlying Notch-induced lineage conversion and reprogramming of mammary cells

Project description:Transcriptional landscapes underlying Notch-induced lineage conversion and reprogramming of mammary cells

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β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects.

Project description:Objective Notch signaling is re-activated in β cells from obese mice, and is causal to β cell dysfunction. Notch activity is determined in part by expression of transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant β cell dysfunction in obese mice. Methods We assessed expression of Notch pathway components in diet-induced obese (DIO) or leptin receptor-deficient (db/db) mice, and performed single cell RNA sequencing (scRNAseq) in islets from patients with and without type 2 diabetes (T2D). We generated and performed glucose tolerance testing in inducible, β cell-specific Jagged1 gain-of- and loss-of-function mice. We also tested effects of monoclonal neutralizing antibodies to Jagged1 in glucose-stimulated insulin secretion (GSIS) assays in isolated islets. Results Jag1 was the only Notch ligand that tracked with increased Notch activity in DIO and db/db mice. Consistently, JAG1 tracked with Notch activity in metabolically inflexible β cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from DIO and db/db mice potentiated GSIS ex vivo. To demonstrate if β cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible β cell-specific Jag1 transgenic mice (β-Jag1TG), which showed impaired glucose intolerance due to reduced GSIS. However, β cell-specific Jagged1 loss-of-function (β-Jag1KO) did not protect against HFD-induced insulin secretory defects or glucose intolerance. Conclusions Jagged1 is increased in islets from obese mice and in patients with T2D, and neutralizing Jagged1 antibodies lead to improved GSIS, suggesting that inhibition of Jagged1-Notch signaling may have therapeutic benefit. However, genetic loss-of-function experiments suggest that β cells are not a likely source of the Jagged1 signal.

2024-02-23 | GSE249170 | GEO

Notch-dependent functional conversion of RUNX factors regulates the initiation of T-lineage program [RNA-seq]

Project description:RUNX factors play an essential role in the development of T cell. Dynamic interacting partner switching of RUNX1 induces the redeployment of RUNX1 at the T-lineage commitment checkpoint. Here, we attempted to reveal functional differences in RUNX factors between lymphoid progenitor (LP) and Noth-stimulated the earliest T progenitor stage, phase1. We identified CTCF as a LP-specific RUNX1-interacting partner. Indeed, LP-specific RUNX1 binding genomic sites had significantly enriched CTCF consensus motif and co-occupied with CTCF. After Notch stimulation, Notch1-IC directly interacted with RUNX1 and recruited it to the Notch-regulated T-signature gene loci with the Mediator/p300 transcriptional activation complex. CRISPR/Cas9-mediated stage-specific deletion of RUNX factors and its binding partners revealed that the RUNX1/CTCF complex in LP and the RUNX1/Mediator/p300 complex in phase1 negatively and positively regulate T-signature genes expression, respectively. Our results indicate that the Notch-mediated functional conversion of RUNX factors; re-organization of protein complexes and redeployment of genomic binding sites, has a crucial role in the initiation of T-lineage program.

2025-10-14 | GSE291465 | GEO

Notch-dependent functional conversion of RUNX factors regulates the initiation of T-lineage program [ChIP-seq]

2025-10-14 | GSE291464 | GEO

Notch

Project description:Notch

| PRJNA988118 | ENA