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Expression data from bone marrow derived granulocyte monocyte precursors (GMPs) from wt -, Gfi1 knock-out -, human-Gfi1-SNP36N knock in and human wt-Gfi1 knock in mice

ABSTRACT: The incidence of cancer is not only influenced by exposure to environmental factors such as toxic substances and chemotherapy, but is also a result of individual predispositions. Single Nucleotide Polymorphisms (SNPs) represent one such individual predisposition to cancer1. Gfi136N is a SNP in the coding region of the gene “Growth factor independence 1 (Gfi1)” predisposing to development of Acute myeloid leukemia (AML). However, the mechanisms how this polymorphism is associated with AML are unknown. Here we present a mouse model in which the presence of Gfi136N leads to altered epigenetic modifications in the myeloid progenitor fraction “Granulocytic Monocytic Progenitor (GMP)” and demonstrates how this might predispose to AML. Presence of Gfi136N leads to a different epigenetic programming of the GMPs resulting in higher levels of the leukemogenic transcription factor Hoxa9. To our knowledge, this is the first mouse model of a SNP leading to epigenetic changes. Thus, SNPs not only result in an altered structure or expression level of certain proteins but here we show that SNPs might also lead to different cancer related epigenetic modifications. We used microarrays to detail the changes in the program of gene expression of GMPs induced by the knock in of human Gfi1 variants in the mouse Gfi1 locus

ORGANISM(S): Mus musculus

PROVIDER: GSE25551 | GEO | 2012/11/22

SECONDARY ACCESSION(S): PRJNA134033

REPOSITORIES: GEO

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Project description:GFI1 is a transcriptional repressor protein that plays an essential role in HSCs development, lymphoid and myeloid differentiation and Acute Myeloid Leukaemic (AML) pathogenesis. Low expression levels of GFI1 is associated with a poor prognosis in AML development. In addition, a single nucleotide polymorphism (SNP) variant of GFI1 results in the generation of GFI1 protein with asparagine (N) instead of serine (S) at the 36th amino acid position, known as GFI136N. Expression of the GFI1-36N allele leads as well to poor prognosis and promotes AML development. In this study, we demonstrated with the help of RNAseq transcriptomic analysis that the presence of GFI1-36N is associated with increased frequency of chromosomal aberrations and mutational burden in murine and human AML cells. In particular, GFI1-36N modulates DNA repair pathways, O6-methylguanine-DNA-methyltransferase (MGMT)-mediated repair and homologous recombination repair (HR). Mechanistically, GFI1-36N exhibits impaired binding to Ndrg1 promoter element compared to GFI1-36S (wild type), causing decreased NDRG1 levels, consequently leading to suppression of MGMT expression, imprinted at the transcriptome and proteome, thus leaving the AML cells vulnerable to DNA damaging agents. Furthermore, we showed that a low expression level of GFI1 in leukemic cells is associated with high OXPHOS and enhanced glutamine metabolism. However, we hypothesise that the observed metabolic phenotype is mediated through FOXO1 protein. RNAseq transcriptomic analysis revealed higher Foxo1 mRNA expression levels with lower GFI1 expression, providing the first hint of Foxo1 as a potential target gene of GFI1 protein. The mRNA and protein levels of high Foxo1 with reduced GFI1 expression was confirmed by RT-PCR and western blot, respectively. In addition, CHIPseq and ATACseq analysis further proved that Foxo1 is a potential target gene of GFI1. In summary, we show that GFI1 plays a role during DNA repair and metabolism and thus provides critical insights into a novel therapeutic option for AML patients carrying the GFI1-36N variant or having a low expression level of GFI1.

Project description:MDS is characterized by a disturbed function of the myeloid lineage of the hematopoietic system that may transform to AML, a malignant disease of the myeloid compartment. Epigenetic and genetic aberrations contribute to the initiation and progression of MDS/AML. GFI1 is a transcriptional repressor, which regulates expression of its target genes by, among other approaches, recruiting HDACs to its target genes to remove histone 3 lysine 9 (H3K9) acetylation, a marker for active gene expression. Low levels of GFI1 expression and deletion of one GFI1 allele contribute to MDS/AML development in human patients and are associated with a specific gene expression signature and inferior prognosis. To explore the mechanism behind this, we used a mouse strain, which expresses GFI1 only at 5-10% of the normal level (GFI1-Knock-down (KD)). Knock-down of GFI1 or loss of one murine Gfi1 allele reduced latency and increased incidence of AML in different murine models of human MDS/AML development. On the epigenetic level, KD of Gfi1 lead to increased amount of H3K9 acetylation, resulting in increased expression of genes involved in AML development. On a translational level both murine as well as human AML cells with low expression of GFI1 are resistant to standard epigenetic therapy. We show that treatment with histone acetyltransferase inhibitors might be a novel treatment approach for low Gfi1-expressing blast cells. GFI1 has a dose dependent role in myeloid malignancies and is a biomarker for therapeutic intervention. We used microarrays to detail the global programme of gene expression in bone marrow cells of Nup98HoxD13 leucemic mice and identified distinct classes of up-regulated genes during this process. Bone marrow cells of leukemic mice (from KI & KD Nup98HoxD13 mice) were collected for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain homogeneous populations of leukemic cell population, so we took samples of mice which had the same age.

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Expression data from bone marrow derived granulocyte monocyte precursors (GMPs) from wt -, Gfi1 knock-out -, human-Gfi1-SNP36N knock in and human wt-Gfi1 knock in mice

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