Gene expression changes in NRASG12D, NUP98-NSD1 and NUP98-NSD1+NRASG12D transformed mouse bone marrow cells (in vitro).
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ABSTRACT:
PROVIDER: PRJNA638683 | ENA |
REPOSITORIES: ENA
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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
Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Experiment Overall Design: Total RNA was extracted from stably transformed progenitors cultured in vitro and the expression levels of mRNA transcripts quantified using the Affymetrix GeneChip Mouse Genome 430 2.0 array, as previously described. The GEO database accession numbers: for progenitors immortalized by HoxA9 (GSM190542, GSM190546, GSM190547); for progenitors immortalized by coexpressed HoxA9 plus Meis1 (GSM190548, GSM190549, GSM190550); for progenitors immortalized by NUP98-NSD1 (GSM190551, GSM190552, GSM190553); and for progenitors immortalized by MLL-ENL (GSM190554). Experiment Overall Design: NOTE: CEL files and dChip data were requested by GEO but not provided.
2008-06-11 | E-GEOD-10071 | biostudies-arrayexpress
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:Interactome studies of NUP98-NSD1 and its mutated forms in HEK293 cells
2022-02-17 | PXD026020 | Pride
Project description:The NUP98::NSD1 fusion gene is associated with extremely poor prognosis in patients with acute myeloid leukemia (AML). NUP98::NSD1 induces self-renewal and blocks differentiation of hematopoietic stem cells, leading to leukemia development. Despite its association with poor prognosis, targeted therapy for NUP98::NSD1-positive AML is lacking, as the details of NUP98::NSD1 function are unknown. Here, we generated 32D cells (a murine interleukin-3 (IL-3)-dependent myeloid progenitor cell line) expressing mouse Nup98::Nsd1 to explore the function of NUP98::NSD1 in AML, including by comprehensive gene expression analysis. We identified two properties of Nup98::Nsd1+ 32D cells in vitro: first, Nup98::Nsd1 promoted blocking of AML cell differentiation, consistent with a previous report; second, Nup98::Nsd1 increased dependence on IL-3 for cell proliferation, due to overexpression of the alpha subunit of the IL-3 receptor (IL3-RA, also known as CD123). Consistent with our in vitro data, IL3-RA was also up-regulated in samples from patients with NUP98::NSD1-positive AML. These results highlight CD123 as a potential new therapeutic target in NUP98::NSD1-positive AML.
2022-10-25 | GSE216409 | GEO
Project description:Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy driven largely by gene mutations and epigenetic modifications. The Nucleoporin 98kDa (NUP98) gene is a component of the nuclear pore complex that also plays a role as an intranuclear transcription scaffold. Fusion genes involving NUP98 have been recognized in a wide array of hematologic malignancy, most commonly AML4. Among over 30 partner genes known to be fused to NUP98 in human leukemia, NSD1 (for Nuclear receptor-binding SET Domain protein 1) (NSD1) is the most common. Patients with NUP98::NSD1 gene fusions have a poor prognosis, and the leukemic blasts frequently have an internal tandem duplication (ITD) of the FMS-related tyrosine kinase 3 gene (FLT3) gene accompanying the NUP98::NSD1 fusion. Previous reports have utilized BM transduction with retroviral vectors followed by transplantation into recipient mice to model AML driven by a NUP98::NSD1 fusion. Given that genetically engineered mice offer certain advantages over retroviral transduction models, such as consistent transgene expression and integration effects, lack of ionizing radiation, and transferability between investigators, we generated NUP98::Nsd1 transgenic mice.
2023-07-12 | GSE229501 | GEO
Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Keywords: expression analysis
2008-01-04 | GSE10071 | GEO
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 report Illumina next generation RNA sequencing (RNAseq) of NUP98-HOXA9 in vitro transformed murine LSKs upon genetic deletion of Mll1. These gene expression data illustrate that Mll1 regulates Hoxa, Hoxb and Meis1 expression in NUP98-HOXA9 transformed murine BM cells.
2016-12-11 | GSE75997 | GEO
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