Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA340369 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4081410.fastq.gz | Fastqsanger.gz | |||
| SRR4081420.fastq.gz | Fastqsanger.gz | |||
| SRR4081411.fastq.gz | Fastqsanger.gz | |||
| SRR4081421.fastq.gz | Fastqsanger.gz | |||
| SRR4081412.fastq.gz | Fastqsanger.gz |
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Project description:Evi1 is essential for proliferation of hematopoietic stem cells and implicated in the development of myeloid disorders. Particularly, high Evi1 expression defines one of the largest clusters in acute myeloid leukemia and is significantly associated with extremely poor prognosis. Improvement of the therapeutic outcome of leukemia with activated Evi1 is one of the most challenging issues. However, mechanistic basis of Evi1-mediated leukemogenesis has not been fully elucidated. Here we show that Evi1 directly represses PTEN transcription in the murine bone marrow, which leads to activation of AKT/mTOR signaling. In a murine bone marrow transplantation model, Evi1 leukemia showed remarkable sensitivity to an mTOR inihibitor rapamycin. Furthermore, we found that Evi1 binds to several polycomb group proteins and recruits polycomb repressive complexes for PTEN downregulation, which reveals a novel epigenetic mechanism of AKT/mTOR activation in leukemia. Expression analyses and chromatin immunoprecipitation assays using human samples indicate that our findings in mice models are recapitulated in human leukemic cells. Dependence of Evi1-expressing leukemic cells on AKT/mTOR signaling provides the first example of targeted therapeutic modalities that suppress the leukemogenic activity of Evi1. The PTEN/AKT/mTOR signaling pathway and the Evi1-polycomb interaction can be promising therapeutic targets for leukemia with activated Evi1. Gene expression analysis for the purpose of identifying the target genes of Evi1 in primary bone marrow. 5-FU-primed mononuclear bone marrow cells harvested from C57/B6 mice were retrovirally transduced with Evi1-GFP or GFP. GFP positive cells were sorted and analyzed by Affymetrix® Mouse Genome 430 2.0 Array® for gene expression. Four independent experiments were performed.
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Project description:Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable with current chemotherapy regimens. Insight into the mechanism by which EVI1 drives myeloid transformation is needed to target EVI1 in those leukemias. Here we demonstrate recurrent interaction of CTBP1/2 with a unique PLDLS motif in EVI1, which is indispensable for leukemic transformation of 3q26/MECOM rearranged AML. A PLDLS competitor construct outcompetes EVI1 to CTBP1/2 binding and inhibits AML proliferation in xenotransplant models. This proof-of-concept study opens the possibility to target one of the most incurable forms of AML using specific inhibitors directed to EVI1/CTBP1/2 interaction. Our findings have important implications for other tumour types with aberrant expression of EVI1 or other oncogenic transcription factors that also depend on CTBP1/2 interaction.
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