Expression data from AML1-ETO (AE)-expressing murine bone marrow (BM) cells treated with retinoids
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE39883 | GEO | 2012/12/25
SECONDARY ACCESSION(S): PRJNA171940
REPOSITORIES: GEO
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Project description:AE-expressing murine BM cells treated with all-trans retinoic acid (ATRA) in semi-solid methycellulose-based cultures show an increase in self-renewal capacity whilst treatment with a specific RARa agonist NRX195183 reduces their clonogenicity. Gene expression analysis was performed to further investigate the molecular mechanisms underlying these observations. Upregulated gene sets were identified in the ATRA-treated AE BM cells. 3 C57Bl/6 AML1-ETO-stop/+/Mx-Cre+ mice (#D203, 218 and 220) were treated with polyI:C to excise the stop codon allowing AML1-ETO expression. 2-4 weeks following completion of polyI:C administration, mice were euthanised and BM cells harvested. BM cells were cultured in semi-solid methylcellulose assays with cytokines for 2 weeks; then cells were harvested, pooled and replated in suspension cultures containing cytokines and the respective treatments - DMSO (control), ATRA and the specific RARa agonist NRX195183. At the 8 hour (8H) and 24 hour (24H) timepoints, cells were harvested for RNA extraction and processing.
2012-12-25 | E-GEOD-39883 | biostudies-arrayexpress
Project description:Blocking the self-renewal of pre-leukemia stem cells could prevent AML relapse. In this study we show that FOXO1 is an essential self-renewal factor in leukemic and pre-leukemic cells expressing the t(8;21)-associated oncogene AML1-ETO (AE). FOXO1 is consistently upregulated in t(8;21) AML and functions as a critical oncogenic mediator rather than a tumor suppressor. Expression of FOXO1 in human CD34+ cells promotes a pre-leukemic state, partially phenocopying the cellular and transcriptional effects of AE expression. The DNA binding ability of FOXO1 is essential for these features. AE and FOXO1 co-occupy the majority of their binding sites, whereby FOXO1 binds to multiple crucial self-renewal genes and is required for their activation. In concordance with this observation, loss of FOXO1 inhibits the long-term proliferation and clonogenicity of AE cells. Thus, increased FOXO1 represents a new mechanism for acquiring aberrant self-renewal by pre-leukemia stem cells and provides a novel target for therapeutic intervention.
2017-10-30 | GSE80773 | GEO
Project description:High-resolution proteomic analysis of acute myeloid leukemia (AML) stem cells identified phospholipase C- and Ca++-signaling pathways to be differentially regulated in AML1-ETO (AE) driven leukemia. Phospholipase C gamma 1 (Plcg1) could be identified as a direct target of the AE fusion. Genetic Plcg1 inactivation abrogated disease initiation by AE, reduced intracellular Ca++-release and inhibited AE-driven self-renewal programs. In AE-induced leukemia, Plcg1 deletion significantly reduced disease penetrance, number of leukemia stem cells and abrogated leukemia development in secondary recipient hosts. In human AE-positive leukemic cells inactivation of Plcg1 reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for maintenance of murine and human hematopoietic stem- and progenitor cells (HSPCs). Pharmacologic inhibition of Ca++-signaling downstream of Plcg1 resulted in impaired proliferation and self-renewal capacity in AE-driven AML. Thus, the Plcg1 pathway represents a novel specific vulnerability of AE-driven leukemia and poses an important new therapeutic target.
2022-01-12 | PXD011251 | Pride
Project description:Purpose: The goal of this study is to decipher the molecular basis of TBLR1-RARa-expressing APL and to explore potential treatment target based on NGS-derived transcriptome profiling (RNA-seq) Methods: RNA-seq was performed to analyze differential gene expression between GFP+ cells from BM of TBLR1-RARa mice (TR1 and TR9) and lin- cells from BM of control mice (Control). Results: Transcriptome profiling associates with leukemic phenotype and predicts HDACi response in TR-induced APL. Conclusions: Our study represents the first bioinformatic analysis of DEGs from APL mice with TBLR1-RARa fusion gene, generated by RNA-seq technology. Transcriptome profiling associates with leukemic phenotype of differentiation block and predicts drug response to HDAC inhibitors.
2021-06-08 | GSE174247 | GEO
Project description:In an effort to identify novel drugs targeting fusion-oncogene induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE) driven AML we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem- and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO positive leukemic stem cells.
2021-11-04 | PXD026374 | Pride
Project description:Leukemia stem cells are characterized by aberrant self-renewal capacity. Targeting oncogenic fusions that mediate this aberrant self-renewal capacity remains a therapeutic challenge. The t(8;21) translocation, resulting in the oncogenic fusion AML1-ETO (AE, RUNX1-RUNXT1) is among the most common chromosomal rearrangements found in acute myeloid leukemia (AML). By conducting high-resolution proteomic analysis on myeloid leukemia stem cells we identified Phospholipase C- and Ca++-signaling pathways to be differentially regulated in AE/t(8;21) AML. Phospholipase C gamma 1 (Plcg1) was specifically, and highly expressed in t(8;21) AML and could be identified as a direct target of the AML1(RUNX1)-ETO fusion. Genetic inactivation of Plcg1 resulted in abrogation of disease initiation by AE, reduction of intracellular Ca++ release and loss of AE-driven self-renewal programs. Plcg1 deletion after onset of AE-induced leukemia significantly reduced disease penetrance, number of leukemia stem cells and resulted in abrogation of leukemia development in secondary recipients. Inactivation of Plcg1 in human AE-positive AML cells by RNAi reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for steady state hematopoiesis and maintenance of murine and human hematopoietic stem cells (HSC). Translationally, we used pharmacologic inhibition of Ca++ signaling downstream of Plcg1 in AE-driven AML and this resulted in impaired proliferation and self-renewal capacity. The Plcg1 pathway represents a novel, specific vulnerability of AE-driven leukemia and represents an important new therapeutic target.
2019-09-02 | GSE122062 | GEO
Project description:Leukemia stem cells are characterized by aberrant self-renewal capacity. Targeting oncogenic fusions that mediate this aberrant self-renewal capacity remains a therapeutic challenge. The t(8;21) translocation, resulting in the oncogenic fusion AML1-ETO (AE, RUNX1-RUNXT1) is among the most common chromosomal rearrangements found in acute myeloid leukemia (AML). By conducting high-resolution proteomic analysis on myeloid leukemia stem cells we identified Phospholipase C- and Ca++-signaling pathways to be differentially regulated in AE/t(8;21) AML. Phospholipase C gamma 1 (Plcg1) was specifically, and highly expressed in t(8;21) AML and could be identified as a direct target of the AML1(RUNX1)-ETO fusion. Genetic inactivation of Plcg1 resulted in abrogation of disease initiation by AE, reduction of intracellular Ca++ release and loss of AE-driven self-renewal programs. Plcg1 deletion after onset of AE-induced leukemia significantly reduced disease penetrance, number of leukemia stem cells and resulted in abrogation of leukemia development in secondary recipients. Inactivation of Plcg1 in human AE-positive AML cells by RNAi reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for steady state hematopoiesis and maintenance of murine and human hematopoietic stem cells (HSC). Translationally, we used pharmacologic inhibition of Ca++ signaling downstream of Plcg1 in AE-driven AML and this resulted in impaired proliferation and self-renewal capacity. The Plcg1 pathway represents a novel, specific vulnerability of AE-driven leukemia and represents an important new therapeutic target.
2022-05-02 | GSE120828 | GEO
Project description:Mechanisms of immunoediting and immune evasion in AML1-ETO (AE) NrasG12D AML.
| PRJNA692606 | ENA
Project description:Transcriptome analysis by RNAseq of human CD34+ hematopoietic stem and progenitor cells transduced with empty vector control(MIT), AML1-ETO (AE), wildtype FOXO1 (F WT) or FOXO1 DNA binding deficient mutant (F DB). We find wildtype FOXO1 partially recapitulates gene signature of AML1-ETO
2017-12-15 | GSE81084 | GEO
Project description:AML1-ETO is the chimeric protein product of t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the nervy homology region (NHR) 3 domain, which shares homology with A-kinase anchoring proteins and interacts with the regulatory subunit of type II cAMP-dependent protein kinase A (PKA(RII?)). We determined the solution structure of a complex between the AML1-ETO NHR3 domain and PKA(RII?). Based on this structure, a key residue in AML1-ETO for PKA(RII?) association was mutated. This mutation did not disrupt AML1-ETO's ability to enhance the clonogenic capacity of primary mouse bone marrow cells or its ability to repress proliferation or granulocyte differentiation. Introduction of the mutation into AML1-ETO had minimal impact on in vivo leukemogenesis. Therefore, the NHR3-PKA(RII?) protein interaction does not appear to significantly contribute to AML1-ETO's ability to induce leukemia.
| S-EPMC2945414 | biostudies-literature