Transcriptome analysis of bone marrow cells of Evi1-overexpressing leukemia mouse
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA616291 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11449155.fastq.gz | Fastqsanger.gz | |||
| SRR11449156.fastq.gz | Fastqsanger.gz | |||
| SRR11449157.fastq.gz | Fastqsanger.gz | |||
| SRR11449158.fastq.gz | Fastqsanger.gz | |||
| SRR11449159.fastq.gz | Fastqsanger.gz |
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Project description:Puropose: To detemine transcriptome profile of Evi1-overexpressing leukemia cells by RNA sequencing Method: RNA samples were isolated from GFP+Lin-c-kit+ mouse bone marrow cells
2020-03-31 | GSE147736 | GEO
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.
2010-07-08 | E-GEOD-22434 | biostudies-arrayexpress
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.
2010-06-18 | GSE22434 | GEO
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.
2024-05-21 | PXD048760 | Pride
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.
2023-07-13 | PXD043333 | Pride
Project description:Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia
| PRJNA787920 | ENA
Project description:RATIONALE: Giving high doses of chemotherapy drugs, such as busulfan and cyclophosphamide, before a donor bone marrow transplant helps stop the growth of cancer cells. It may also stop the patient’s immune system from rejecting the donor’s stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient’s bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body’s normal cells. Giving cyclosporine, methylprednisolone, and methotrexate after transplant may stop this from happening.
PURPOSE: This clinical trial studies high-dose busulfan and high-dose cyclophosphamide followed by donor bone marrow transplant in treating patients with leukemia, myelodysplastic syndrome, multiple myeloma, or recurrent Hodgkin or Non-Hodgkin lymphoma.
| 2093228 | ecrin-mdr-crc
Project description:Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 at MECOM drive inv(3)/t(3;3) myeloid leukemias and revealed MECOM germline mutations in patients with MECOM-associated bone marrow failure syndromes. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 which is frequently present in inv(3)/t(3;3) AML and directly contributes to leukemic transformation. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21;26) allele hastened leukemogenesis in vivo. These data provide a mechanistic basis for the frequent co-occurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
2022-06-21 | GSE190653 | GEO
Project description:Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 at MECOM drive inv(3)/t(3;3) myeloid leukemias and revealed MECOM germline mutations in patients with MECOM-associated bone marrow failure syndromes. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 which is frequently present in inv(3)/t(3;3) AML and directly contributes to leukemic transformation. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21;26) allele hastened leukemogenesis in vivo. These data provide a mechanistic basis for the frequent co-occurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
2022-06-21 | GSE190652 | GEO
Project description:Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 at MECOM drive inv(3)/t(3;3) myeloid leukemias and revealed MECOM germline mutations in patients with MECOM-associated bone marrow failure syndromes. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 which is frequently present in inv(3)/t(3;3) AML and directly contributes to leukemic transformation. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21;26) allele hastened leukemogenesis in vivo. These data provide a mechanistic basis for the frequent co-occurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
2022-06-21 | GSE190655 | GEO