The expression profiles of AML cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35159 | GEO | 2012/01/18
SECONDARY ACCESSION(S): PRJNA150785
REPOSITORIES: GEO
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Project description:EVI1 is one of the famous poor prognostic markers for a chemotherapy-resistant acute myeloid leukemia (AML). To identify molecular targets on the surface of leukemia cells with EVI1high expression, we compared the gene expression profiles of several AML cell lines by DNA microarray To search for novel molecular targets in refractory myeloid leukemia with high EVI1 expression, we initially analyzed the gene expression profiles of 12 human myeloid cell lines. Four cell lines with chromosome 3q26 abnormalities (UCSD/AML1, HNT-34, Kasumi-3 and MOLM-1) expressed EVI1High, and eight myeloid cell lines without chromosome 3q26 abnormalities (HEL, HL-60, K052, THP-1, FKH-1, K051, NH and OIH-1) expressed low levels of EVI1 (EVI1Low)
2012-01-18 | E-GEOD-35159 | biostudies-arrayexpress
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.
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Project description:MLL-fusion proteins can induce acute myeloid leukemias (AML) from either hematopoietic stem cells (HSC) or granulocyte macrophage progenitors (GMP), but it remains unclear if the cell of origin influences the biology of the resultant leukemia. MLL-AF9 transduced single HSC or GMP could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSC or GMP had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC derived LGMP. The gene expression signature of LGMP derived from HSC was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5’-mC levels were elevated in HSC-derived leukemias as compared to GMP-derived leukemias. This mirrored a difference seen in 5-mC between MLL-rearranged human leukemias that are either EVI1-positive or EVI1-negative. Finally, HSC derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state, and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias. Differential DNA methylation between of LSC isolated from murine HSC and GMP derived AMLs
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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+).
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Project description:Acute myeloid leukemia (AML) patients are primarily resistant to induction chemotherapy in 20-50%. Previously it has been shown that resistance to the first cycle of induction chemotherapy is an independent prognostic factor. We investigated whether resistance to chemotherapy can be represented by gene-expression profiling, and which genes are associated with resistance. cDNA microarrays containing ~41.000 features were used to compare the gene-expression profile of AML blasts between 33 patients with good or poor response to induction chemotherapy. Data generated by cDNA-arrays were confirmed by quantitative RT-PCR. Using Significance Analysis of Microarrays, we identified a characteristic gene-expression profile which distinguished good- from poor-response AML samples. In hierarchical clustering analysis poor responders clustered together with normal CD34+ cells. Moreover, 13/40 (32.5%) genes highly expressed in poor responders are also overexpressed in hematopoietic stem/progenitor cells. Prediction analysis using 10-fold crossvalidation revealed 80% overall accuracy. Using the treatment response signature to predict the outcome in an independent test set of 104 AML patients, samples were separated into two subgroups with significantly inferior response rate (43.5% vs. 66.7%, P=.044), significantly shorter event-free and overall survival (P=.01 and P=.03, respectively) in the poor-response compared to the good-response signature group. In multivariate analysis, the treatment-response signature was an independent prognostic factor (hazard ratio, 2.1, 95 percent-confidence interval 1.2 to 3.6, P=.006). Resistance to chemotherapy in AML can be identified by gene-expression profiling before treatment and seems to be mediated by a transcriptional program active in hematopoietic stem/progenitor cells. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs
2006-02-01 | GSE4137 | GEO
Project description:The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens, we identified selective and pan-histone deacetylase inhibitors (HDACis) as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, we dissected the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstituted the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogated EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACi-based combination therapies in patients with 3q26 AML.
2024-04-01 | GSE256076 | GEO
Project description:The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens, we identified selective and pan-histone deacetylase inhibitors (HDACis) as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, we dissected the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstituted the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogated EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACi-based combination therapies in patients with 3q26 AML.
2024-04-01 | GSE256040 | GEO
Project description:Selective and pan-histone deacetylase inhibitors (HDACis) emerged at the intersection of these approaches. HDACis suppress EVI1 expression and preferentially impair leukemia proliferation in 3q26 AML compared to other leukemia subtypes in multiple preclinical models. To understand this mechanism of action, we dissected the expression dynamics of the bone marrow leukemia cells of patients treated with hit list compounds, reconstituted with the chromatin-associated co-transcriptional complex of EVI1 by rapid immunoprecipitation mass spectrometry (RIME) in human 3q26 AML models; we focused on the role of the proliferation-associated 2G4 (PA2G4) protein. We demonstrated that genetic and HDACi-mediated suppression of EVI1 modulates MYC and that PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis. Genetic and small molecule inhibition of PA2G4 abrogated EVI1 and, consequently, MYC in 3q26 AML models, including in patient-derived leukemia xenografts. In conclusion, our work positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and, at this time, urges the use of upfront HDACi-based combination therapies in patients with 3q26 AML.
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Project description:The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens, we identified selective and pan-histone deacetylase inhibitors (HDACis) as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, we dissected the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstituted the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogated EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACi-based combination therapies in patients with 3q26 AML.
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