EVI1 in acute myeloid leukemia triggers metabolic reprogramming associated with leukemogenesis
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PROVIDER: PRJNA484401 | ENA |
REPOSITORIES: ENA
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Project description:Overexpression of Ecotropic Virus Integration site 1 protein homolog (EVI1) in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. We used an extracellular flux analyze to examine metabolic changes during leukemia development in a mouse model of MLL-r AML expressing high levels of Evi1 (Evi1+).
2018-08-04 | GSE118096 | GEO
Project description:Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1+MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1+ leukemia cells may aid development of treatments for EVI1+MF9 refractory leukemia.
| S-EPMC7395283 | biostudies-literature
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: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:Chromosomal rearrangements involving EVI1 (MECOM) define a subtype of acute myeloid leukemia (AML) that is associated with a two-year survival rate of <10%. Gene regulatory functions of EVI1 are largely elusive and no targeted therapeutics exist. We developed experimentally tractable murine and human leukemia models that recapitulate phenotypic and transcriptional features of EVI1-rearranged AML and enable large-scale loss-of-function screens. We characterize EVI1-controlled transcriptional programs in cell culture and in vivo, perform CRISPR screens and identify the ETS-related transcription factor ERG as the only gene that is specifically required for EVI1-driven AML. ERG is transcriptionally activated by EVI1 and overexpressed in EVI1-rearranged AML patients. ERG suppression selectively induces terminal differentiation of leukemia cells. EVI1 becomes dispensable for leukemia cells upon ectopic expression of ERG, indicating that key functions of EVI1 are mediated through aberrant activation of ERG. Interfering with this regulatory axis may therefore provide new entry points for rational therapies.
2022-10-11 | GSE195497 | GEO
Project description:The EVI1 gene codes for a transcription factor with important roles in development and leukemogenesis. Overexpression of EVI1 in acute myeloid leukemia (AML) is one of the worst prognostic factors in patients with and without 3q26 rearrangements. Evi1 acts in several pathways through the interaction with proteins with important functions in hematopoiesis; however, the role of Evi1 as a transcription factor is not well known, and only some Evi1 target genes have been identified in mice. Our aim was to investigate the pathways and direct target genes of EVI1. Differential expression profiles after EVI1 knockdown allowed us to identify 125 genes involved in cell growth, differentiation and signal transduction that could be related to EVI1. Moreover, we looked for potential EVI1 binding sites within the region 1000 bp upstream of the transcription start sites of all human genes. We selected a total of 70 genes from the bioinformatics search, genes related to EVI1 by literature, and genes differentially expressed in the expression array. ChIP in the TF1 and HEL cell lines with two EVI1 antibodies demonstrated that EVI1 binds to the proximal promoter regions of 18 of these genes, most of them involved in important differentiation and proliferation pathways, confirming the important role of EVI1. Interestingly, EVI1 binds to the proximal region of its promoter, suggesting that it could be regulating its own transcription. Further functional studies are in progress. These data provide a starting point for further studies aimed at uncovering the mechanism for EVI1-induced transformation leukemias. Keywords: Gene expression analysis after transient knockdown of EVI1. 12 samples. Three replicates per experimental condition. Two cell lines (HTB-58, TF-1). Transient EVI1 knockdown using anti-EVI1 siRNA molecules vs. control siRNA.
2012-09-30 | E-GEOD-16238 | biostudies-arrayexpress
Project description:The transcription factor Evi1 is essential for the formation and maintenance of hematopoietic stem cells, and induces clonal dominance with malignant progression upon constitutive activation by chromosomal rearrangements or transgene integration events. To understand the immediate and adaptive response of primary murine hematopoietic cells to the transcriptional upregulation of Evi1, we developed an inducible lentiviral vector system with a robust expression switch. We found that Evi1 delays differentiation and promotes survival in myeloid culture conditions, orchestrating a battery of genes involved in stemness (Aldh1a1, Ly6a [Sca1], Abca1, Epcam, among others). Importantly, Evi1 suppresses Cyclins and Cyclin-dependent kinases (Cdk), while it upregulates Cdk inhibitors, inducing quiescence in various proliferation-inducing cytokine conditions and operating in a strictly dose-dependent manner. Hematopoietic cells with persisting Evi1-induction tend to adopt a relatively low expression level. We thus classify Evi1 as a dormancy-inducing oncogene, likely requiring epigenetic and genetic compensation for cell expansion and malignant progression. Evi1 dependent myeloid clone C6 cells expressing a Doxycyclin inducible codon-optimized murine Evi1 were harvested at day 2 after DOX withdrawal and compared to C6 cells under Doxycyclin 1 ug/ml
2014-05-01 | E-GEOD-34755 | biostudies-arrayexpress
Project description:EVI1 drives leukemogenesis through aberrant activation of ERG
| PRJNA800809 | ENA
Project description:The EVI1 gene codes for a transcription factor with important roles in development and leukemogenesis. Overexpression of EVI1 in acute myeloid leukemia (AML) is one of the worst prognostic factors in patients with and without 3q26 rearrangements. Evi1 acts in several pathways through the interaction with proteins with important functions in hematopoiesis; however, the role of Evi1 as a transcription factor is not well known, and only some Evi1 target genes have been identified in mice. Our aim was to investigate the pathways and direct target genes of EVI1. Differential expression profiles after EVI1 knockdown allowed us to identify 125 genes involved in cell growth, differentiation and signal transduction that could be related to EVI1. Moreover, we looked for potential EVI1 binding sites within the region 1000 bp upstream of the transcription start sites of all human genes. We selected a total of 70 genes from the bioinformatics search, genes related to EVI1 by literature, and genes differentially expressed in the expression array. ChIP in the TF1 and HEL cell lines with two EVI1 antibodies demonstrated that EVI1 binds to the proximal promoter regions of 18 of these genes, most of them involved in important differentiation and proliferation pathways, confirming the important role of EVI1. Interestingly, EVI1 binds to the proximal region of its promoter, suggesting that it could be regulating its own transcription. Further functional studies are in progress. These data provide a starting point for further studies aimed at uncovering the mechanism for EVI1-induced transformation leukemias. Keywords: Gene expression analysis after transient knockdown of EVI1.
2012-09-30 | GSE16238 | 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