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Global mouse gene expression data from NUP98-NSD1/FLT3-ITD AML samples and Normal Wild Type whole bone marrow and Normal Wild Type lineage negative bone marrow samples assessed by Bulk RNA-Seq.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE229501 | GEO | 2023/07/12

REPOSITORIES: GEO

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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.

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Global mouse gene expression data from NUP98-NSD1/FLT3-ITD AML samples and Normal Wild Type whole bone marrow and Normal Wild Type lineage negative bone marrow samples assessed by Bulk RNA-Seq.

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