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Synergy of Nras mutation and Nup98-Hoxa10HD gene fusion efficiently preserves the stemness of single hematopoietic stem cells after feeder-free culture

ABSTRACT: Synergy of Nras mutation and Nup98-Hoxa10HD gene fusion efficiently preserves the stemness of single hematopoietic stem cells after feeder-free culture

PROVIDER: PRJNA486840 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7724010_1.fastq.gz	Fastqsanger.gz
	SRR7724010_2.fastq.gz	Fastqsanger.gz
	SRR7724011_1.fastq.gz	Fastqsanger.gz
	SRR7724011_2.fastq.gz	Fastqsanger.gz
	SRR7724012_1.fastq.gz	Fastqsanger.gz

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Synergy of Nras mutation and Nup98-Hoxa10HD gene fusion efficiently preserves the stemness of single hematopoietic stem cells after feeder-free culture

Project description:Hematopoietic stem cell (HSC) gives rise to all the hematopoietic cells. The stemness of HSC is strictly controlled by some transcription factors. Here we show that both of Nras mutation (NrasG12D) and Nup98-Hoxa10HD (NA) improve the transplantation competition ability of HSC. Pathways and differential expression genes analysis show that NrasG12D and NA proteins enhance the competitiveness of HSCs via distinct signaling mechanisms.

2019-08-27 | GSE118809 | GEO

Gene expression changes in NRASG12D, NUP98-NSD1 and NUP98-NSD1+NRASG12D transformed mouse bone marrow cells (in vitro).

Project description:NUP98-NSD1 positive Acute myeloid leukemia (AML) frequently occurs within the pediatric karyotypic normal(CN)-AML cohort. It is often associated with mutations in genes like FLT3, NRAS, WT1 and MYC. Here we have studied the role of NUP98-NSD1 fusion and NRASG12D in leukemia initiation and progression.

2020-10-01 | GSE152244 | GEO

Evaluation of the NUP98-HOXA9 role as oncogenic transcription factor

Project description:To study the oncogenic mechanism triggered by the leukemic fusion protein NUP98-HOXA9, we cloned the cDNA of NUP98-HOXA9 into a retroviral vector (pMSCV-IRES-GFP) and efficiently transduced the HEK293FT human cell line. We performed a ChIP-seq analysis to identify the DNA binding sites of NUP98-HOXA9. These results allowed us to demonstrate that NUP98-HOXA9 regulates the expression of genes involved in the development of Acute Myeloid Leukemia by directly interacting with their enhancer regions. We further investigated the functional contribution to the DNA binding profile of the two moieties that compose the fusion protein. We cloned the coding region of HOXA9 wt and NUP98 wt in the same retroviral vector, established two new cellular models, 293FT-HOXA9 and 293FT-NUP98, and performed separate ChIP-seq analyses. We demonstrated that both moieties contribute importantly to the regulation of the target genes.

2016-12-31 | GSE62586 | GEO

Identification of new therapies for the treatment ofBRAF/NRAS wild type melanomas

Project description:Despite recent therapeutic advances in the management of BRAFV600-mutant melanoma, there is still a compelling need for more effective treatments for patients who developed BRAF/NRAS wild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 17,000 viability curves, with the aim of identifying agents that synergise to kill BRAF/NRAS wild type melanoma cells. From this screen we identified a promising drug combination that efficiency kills 30% of melanoma cell lines. We validated in vivo the synergy of the drug combination and found a potential marker to identify sensitive tumors. We applied a genome-wide CRISPR screening which revealed that resistance mechanisms to the drug combination. In order to investigate the mechanism of drug synergy, we treated sensitive and resistance melanoma cell lines with the single drugs and the drug combination and performed proteome analyses to investigate the changes in total proteins and protein phosphorylation. These analysis highlighted specific pathway deregulations associated to the drug synergy that allowed to get a better understanding of the drug interaction and their efficacy in killing melanoma cell lines.

2022-03-23 | PXD007649 | Pride

Nuclear Condensation of NUP98-Fusion Proteins drives leukemogenic gene expression NUP98-fusion protein drive oncogenic gene expression via nuclear/biomolecular condensation

Project description:NUP98-fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98-fusion proteins share an intrinsically disordered region (IDR) featuring >35 repeats of Phenylalanine-Glycine (FG) in the NUP98 N-terminus. Conversely, C-terminal NUP98-fusion partners often have critical functions in gene control. Given these structural features we hypothesized that mechanisms of oncogenic transformation by NUP98-fusion proteins are hard-wired in their protein interactomes. Affinity purification coupled to mass spectrometry and confocal imaging of five distinct NUP98-fusion proteins revealed that conserved interactors were enriched for proteins involved in biomolecular condensation and that they co-localized with NUP98-fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98-fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins uniquely combine biomolecular condensation with transcriptional control to induce cancer.

2020-12-23 | PXD022518 | Pride

NUP98-HOXA9 acute myeloid leukemia

Project description:Mass Spectrometry analysis of the interactome of the oncoprotein NUP98-HOXA9

2017-07-10 | PXD001828 | Pride

transcriptional profiling of NUP98-CDX1, NUP98-CDX4 and EGFP overexpressing primitive mouse bone marrow cells

Project description:The first genetic hits towards leukemia are thought often to confer to the mutant clone a slight proliferative/survial advantage. These pre-malignant clones can then be maintained under physiological cues in normal pool for long periods. We have searched for this type of first genetic hits and found that ectopic expression of novel nucleoporin 98 (NUP98)-homeodomain fusion proteins in primitive bone marrow cells can induce long-lasting hematopoietic stem cell (HSC) activity in these cells. More specifically, NUP98-CDX1/2 was able to sustain HSC activity with high frequencies despite massive in vitro expansions and in vivo residence. Continual expression of NUP98-CDX1/2 did not perturb lymphoid, myeloid or erythroid/platelet differentiation and NUP98-CDX1/2 was able to reprogram committed progenitors into cells with attributes of HSC. Switching off of NUP98-CDX1/2 expression did not lead to “return” to normal HSC but acute differentiation. Related NUP98-CDX4 induced leukemia with the shortest latency ever reported for HOX transcription factors. In this case switching off of NUP98-CDX4 expression cured the full-blown leukemia and again the cured cells showed only transient repopulating activity in vivo. These two types of pre-leukemic cells generated here will provide useful models for elucidating the self-renewal mechanisms of HSC as well as leukemic stem cells. Total RNA from NUP98-CDX lines was compared to EGFP overexpressing lines. The experiment was done in triplicate.

2012-12-01 | E-GEOD-37900 | biostudies-arrayexpress

NUP98-NSD1 its mutated forms interactome

Project description:Interactome studies of NUP98-NSD1 and its mutated forms in HEK293 cells

2022-02-17 | PXD026020 | Pride

MLL is essential for NUP98-HOXA9-induced leukemia

Project description:Rearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in acute myeloid leukemia and myelodysplastic syndromes. This study demonstrates that the second FG repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with MLL via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited. Molecular analyses indicate that MLL is important for the recruitment of NUP98-HOXA9 to the HOXA locus and for NUP98-HOXA9-induced HOXA gene expression. Our data indicate that MLL is crucial for NUP98-HOXA9 leukemia initiation.

2017-02-28 | GSE93923 | GEO

Genome-wide maps of N_NUP98 and NUP98-TOP1 and MLL1 co-bound targets and their chromatin state in NUP98 fusion transformed cells.

Project description:By performing biotin-mediated chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) for two different NUP98 fusions, we defined the genome-wide direct binding sites of NUP98-TOP1 or N-NUP98. To test whether NUP98 fusions and MLL1 were recruited to the same region of Hox genes promoters, MLL1 ChIP-seq analysis was carried out in murine NUP98-HOXA9 transformed cells using an anti-MLL1n antibody (MO435). In agreement with our results showing that NUP98 fusions interacts with MLL1 in NSL/MLL1 complex, MLL1 binding targets significantly overlap with that of N-NUP98 or NUP98-TOP1 at promoter region and gene body region. In summary, our results confirmed that NUP98 fusions and MLL1 are recruited to the same Hox loci, supporting the notion of the association between NUP98 fusions and NSL/Mll1 complex, suggesting that the recruitment of NUP98 fusions to the Hox gene loci maybe through MLL1.

2016-12-21 | GSE83221 | GEO

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