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Nucleophosmin sustains WNT-driven cell proliferation and tumor initiation in vivo

ABSTRACT: Nucleophosmin sustains WNT-driven cell proliferation and tumor initiation in vivo

PROVIDER: PRJNA1051495 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27184613.fastq.gz	Fastqsanger.gz
	SRR27184614.fastq.gz	Fastqsanger.gz
	SRR27184615.fastq.gz	Fastqsanger.gz
	SRR27184616.fastq.gz	Fastqsanger.gz
	SRR27184617.fastq.gz	Fastqsanger.gz

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Nucleophosmin sustains WNT-driven cell proliferation and tumour initiation in vivo

Project description:Nucleophosmin (NPM1) is a nucleolar protein frequently mutated in haematopoietic malignancies and overexpressed in many solid tumours, but little is known about its functional role in carcinogenesis. Here, we identify NPM1 as a commonly upregulated gene following APC loss in tissues that positively respond to high WNT signalling. High NPM1 expression correlates with increased proliferation in patients with colorectal cancer (CRC). We show that whilst dispensable for adult epithelial tissue homeostasis, NPM1 loss has a profound effect on WNT-driven intestinal and liver tumourigenesis, leading to reduced proliferation and extension of survival. Mechanistically, NPM1 depletion triggers integrated stress response (ISR) and p53 pathway activation. Genetically or chemically blunting these pathways, rescues proliferation following NPM1 loss. Overall, our results demonstrate that NPM1 supports WNT-driven cell proliferation and tumour initiation by attenuating induction of ISR and p53 pathway activation. Being dispensable for homeostasis, NPM1 presents itself as a promising target for cancer therapy in WNT-driven tumours with functional p53, including treatment-refractory KRAS-mutant CRC and hepatic cancers.

2025-08-12 | PXD062969 | Pride

Nucleophosmin sustains WNT-driven cell proliferation and tumor initiation in vivo

Project description:Nucleophosmin (NPM1) is a nucleolar protein frequently overexpressed in many solid tumours with little known about its functional role to support carcinogenesis. Here, we identify Npm1 as a commonly upregulated gene following Apc loss in highly proliferative tissues, and high expression correlates with increased proliferation in CRC patients. We show that NPM1 is dispensable for adult epithelial tissue homeostasis, however, it has a profound effect on WNT-driven intestinal and liver tumourigenesis, leading to reduced proliferation and extension of survival. Mechanistically, NPM1 depletion triggers integrated stress response (ISR) and p53 pathway activation. P53 deletion, or inhibition of the ISR effects, rescue proliferation following NPM1 loss. Overall, our results demonstrate that NPM1 supports WNT-driven cell proliferation and tumour initiation by attenuating p53 pathway activation or induction of ISR. Being dispensable for homeostasis, NPM1 presents as a promising target for cancer therapy in WNT-driven tumours with functional p53, including difficult to treat KRAS-mutant CRC and hepatic cancers.

2024-02-15 | GSE249958 | GEO

Nucleophosmin supports WNT-driven hyperproliferation and tumour initiation

Project description:Nucleophosmin (NPM1), a nucleolar protein frequently mutated in haematopoietic malignancies, is overexpressed in several solid tumours with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated following APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumourigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5’-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this anti-tumourigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumourigenesis by attenuating the integrated stress response (ISR) and p53 activation. Notably, NPM1 expression correlates with elevated WNT signalling and proliferation in human colorectal cancer (CRC), while CRCs harbouring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumours, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.

2025-09-29 | GSE309379 | GEO

Nucleophosmin supports WNT-driven hyperproliferation and tumour initiation

Project description:Nucleophosmin supports WNT-driven hyperproliferation and tumour initiation

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Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia

Project description:Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a pro-apoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage-induced apoptosis is caspase-2-dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c+ cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment in the AKT/mTORC1 and Wnt signaling pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function.

2024-04-17 | GSE249545 | GEO

Non-canonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

Project description:Non-canonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

2020-07-01 | GSE151447 | GEO

CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [HiC]

Project description:CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [HiC]

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Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia

Project description:Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia

| PRJNA1049463 | ENA

Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice

Project description:Comparison of gene expression profiles of mouse bone marrow nucleated cells. All comparisons are made between biological replicates (different mice) derived from animals carrying the Type A cytoplasmic Nucleophosmin mutation (Npm1c) found in human Acute Myeloid Leukaemia. Mice were culled 8 weeks after induction of the conditional Npm1c allele with Mx1-Cre. Whole bone marrow (BM, n=20: 11xNpm1c & 9xWildType) or antibody purified cell fractions (Lin minus, n=6: 4xNpm1c & 2xWildType; B220+, n=5: 3xNpm1c & 2xWildType and Gr1+/Mac1+, n=6: 4xNpm1c & 2xWildType) were studied. Files ("samples") include data from all samples in each comparison.<br>Global profiling was done using Illumina mouse-6 expression beadchip version 2. Data were quantile normalised and analysed using the bioconductor (http://www.bioconductor.org/), lumi (http://www.bioconductor.org/packages/2.0/bioc/html/lumi.html ) and limma packages, then p-value adjusted for multiple testing.

2011-03-15 | E-MEXP-3113 | biostudies-arrayexpress

CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [RNA-seq_CRISPR]

Project description:CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [RNA-seq_CRISPR]

| PRJNA1008731 | ENA