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| Status |
Public on May 12, 2016 |
| Title |
Gfi1 as a new predictive and therapeutical target of MDS/AML |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
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| Summary |
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 carried out ChIP-Seq Analysis of H3K9Ac and RNA-Seq in leukemic cells from mice expressing reduced levels of Gfi1 compared to controls expressing normal levels of the factor.
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| Overall design |
Leukemic cells were extracted from 2 mice from each genotype, Gfi1-KI and Gfi1-KD. H3 and H3K9Ac ChIP-Seq as well as RNA-Seq was carried out on each sample.
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| Contributor(s) |
Hönes J, Botezatu L, Möröy T, Khandampour C |
| Citation(s) |
26847026 |
| |
| Submission date |
Sep 02, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Möröy Tarik |
| E-mail(s) |
tarik.moroy@ircm.qc.ca
|
| Organization name |
Insititut de Recherches Cliniques
|
| Street address |
110 Pine avenue West
|
| City |
Montreal |
| State/province |
Quebec |
| ZIP/Postal code |
H2W 1R7 |
| Country |
Canada |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA294617 |
| SRA |
SRP063272 |
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