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Series GSE195955 Query DataSets for GSE195955
Status Public on Dec 01, 2023
Title Trancriptomic analysis of leukemic bone marrow cells with GFI1 wildtype, GFI1 SNP variant (GFI1-36N) and low level of GFI1 expression
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design The current study includes three mouse models: GFI1-KI mice, which express human GFI1 at the murine Gfi1 locus; GFI1-KD mice, expressing 10-20 % of the human GFI1 gene; and GFI1-36N mice, which express 36N variant of human GFI1 gene. The lineage depleted cells from GFI1-KI, GFI1-KD, and GFI1-36N mice were isolated and retrovirally transduced with MLL-AF9 oncogene, coexpressing GFP reporter protein. The GFP positive cells were FACS sorted and transplanted into lethally irradiated (7+3 Gy) C57BL/6 mice. The total bone marrow cells from the leukemic mice were serially transplanted into sublethally irradiated mice (3 Gy), and the total bone marrow cells from the quaternary transplanted leukemic mice were used for transcriptomic analysis. For the transcriptome analysis of temozolomide treated cells, leukemic bone marrow cells were treated with 50 µg/ml temozolomide 20 h before RNA isolation.
Contributor(s) Khandanpour C, Frank D, Patnana PK, Wei L
Citation(s) 37756525, 37423893
Submission date Feb 02, 2022
Last update date Mar 03, 2024
Contact name Pradeep Kumar Patnana
Organization name University Hospital Muenster
Street address Domagkstr 3
City Muenster
State/province NRW
ZIP/Postal code 48149
Country Germany
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (15)
GSM5856907 S1 GFI1_36S_S_MLL_AF9_1
GSM5856908 S2 GFI1_36S_S_MLL_AF9_2
GSM5856909 S3 GFI1_36S_S_MLL_AF9_3
BioProject PRJNA802740

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Supplementary file Size Download File type/resource
GSE195955_normalized_counts_Gfi1_36N.txt.gz 923.7 Kb (ftp)(http) TXT
GSE195955_normalized_counts_Gfi1_36N_with_or_without_TMZ.txt.gz 905.9 Kb (ftp)(http) TXT
GSE195955_normalized_counts_Gfi1_KD.txt.gz 924.7 Kb (ftp)(http) TXT
GSE195955_normalized_counts_TMZ_treated_leukemic_Gfi1_36N_vs_36S.txt.gz 942.1 Kb (ftp)(http) TXT
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