Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA107201 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We have cloned and characterized a fusion gene NUP98/HHEX1 resulting from t(7;10) from a patient with acute myeloid leukemia (AML). As NUP98/HHEX acts as an aberrant transcriptional activator, putative targets were searched upon transient expression of the fusion in primary murine bone marrow cells. Experiment Overall Design: Murine bone marrow cells were transduced with a retrovirus (MSCV-IRES-GFP, MIG) expressing either NUP98/HHEX or NUP98/HOXA9 (or the empty vector), mRNA was isolated after 72h. Each experiment was performed in triplicates.
2008-06-11 | E-GEOD-10909 | biostudies-arrayexpress
Project description:We have cloned and characterized a fusion gene NUP98/HHEX1 resulting from t(7;10) from a patient with acute myeloid leukemia (AML). As NUP98/HHEX acts as an aberrant transcriptional activator, putative targets were searched upon transient expression of the fusion in primary murine bone marrow cells. Keywords: Comparative analysis of NUP98/HHEX, NUP98/HOX vs. MIG (empty virus) in primary bone marrow cells
2008-04-01 | GSE10909 | GEO
Project description:A novel NUP98/RARG gene fusion in acute myeloid leukemia resembling acute promyelocytic leukemia
2010-10-18 | E-MEXP-2928 | biostudies-arrayexpress
Project description:Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in Acute Myeloid Leukemia (AML) with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has precluded the identification of efficient targeting strategies. We reasoned that shared transcriptional programs of direct NUP98-fusion-protein-mediated gene control converge on actionable targets. To study the transcriptional regulation mediated by NUP98 fusion proteins we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A and NUP98/DDX10. Integration of transcriptional changes after oncogene shutdown in vivo with ChIP-seq data identified a common core of direct NUP98-fusion target genes in AML. Among the direct targets of all NUP98-fusions, the CDK6 (cyclin-dependent kinase 6) gene was highly expressed in mouse and human AML samples. CDK6 loss severely attenuated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was hypersensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing approved CDK4/CDK6 inhibitors as a rationale treatment option for AML patients with NUP98-fusions.
2020-05-08 | GSE134784 | GEO
Project description:NUP98-fusion proteins cause acute myeloid 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, different C-terminal NUP98-fusion partners are often transcriptional and epigenetic regulators. 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 of five distinct NUP98-fusion proteins revealed a conserved set of interactors that was highly enriched for proteins involved in biomolecular condensation. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. In addition, an artificial FG-repeat containing fusion protein was able to phenocopy the induction of leukemic gene expression as mediated by NUP98-KDM5A. Thus, we propose that IDR-containing fusion proteins have evolved to uniquely combine biomolecular condensation with gene control to induce cancer.
2021-02-16 | GSE159037 | GEO
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
Project description:NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML), and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that histone acetyltransferase (HAT) complex proteins including MOZ associate with NUP98 FOs, and that BRPF1, an epigenetic writer that associates with MOZ is a molecular dependency in NUP98::KDM5A AML. Inactivation of Brpf1 as well as HAT complex member Moz, Hbo1, Brd1 or Meaf6 in Nup98::Kdm5a;Vav-Cre cells impaired fitness of NUP98-rearranged cells. MOZ inhibition decreased global H3K23ac levels, displaced FO from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ inhibition decreased leukemic burden in multiple NUP98-rearranged leukemia xenograft models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MOZ is a potentially targetable dependency in NUP98-rearranged AMLs. SIGNIFICANCE STATEMENT MOZ is a member of NUP98 FO condensates with key roles in leukemia phenotypes. MOZ inhibition is effective in multiple preclinical models, including those non-responsive to Menin inhibition. MOZ and Menin inhibition are synergistic in some NUP98-rearranged models, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.
2025-06-03 | PXD058286 | Pride
Project description:To provide the first insight into the pathophysiological relevance of the Nizp1-NSD1 functional association, we targeted this interaction in the context of acute myeloid leukemia driven by the expression of NUP98-NSD1 oncogenic fusion. We expressed NUP98-NSD1 in mouse c-Kit+/Sca-1+/Lin- bone marrow progenitors and knocked down Nizp1 expression by shRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cell lines.
2023-02-07 | GSE209850 | GEO
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
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