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AML1-ETO and CCND2 overexpression¬ cooperate to drive acute myeloid leukemia initiation and progression

ABSTRACT: Increasing numbers of clinical cohorts have detected CCND2 mutations in acute myeloid leukemia (AML), especially in the subtype of AML with t(8;21) translocation. As known, this AML subtype is characterized by the formation of AML1-ETO fusion gene. However, AML1-ETO fusion gene alone is not sufficient to drive leukemia development, additional mutations are required for leukemogenesis. Here, we aim to investigate whether mutated CCND2 can cooperate with AML1-ETO fusion gene to drive leukemia initiation and progression. In our previous study, the conditional AML1-ETO knock-in mouse model (AML1/ETO mouse), which represented a pre-leukemia stage as myeloproliferative neoplasm phenotype, was established. To confirm whether the AML1-ETO and CCND2 mutation can cooperate to drive leukemia, the mice transduction and transplantation model harboring both AML1-ETO and CCND2 gene (both wildtype and mutant) were established. Upon the assessment of the phenotype, biological features and survival of the mice, only the mice overexpressing the AML1-ETO and CCND2 simultaneously were eventually progressed to leukemia. Besides, compared to mice overexpressing AML-ETO gene alone, mTOR and cell cycle-related pathways were significantly enriched in mice harboring both AML1-ETO and CCND2. And the selective mTOR inhibitor, Everolimus, can reduce the leukemia burden and prolong the survival of this group of mice. In conclusion, we confirmed that introduction of the CCND2 gene into the AML/ETO pre-leukemia mice can trigger the development of leukemia. We also confirmed that CCND2 overexpression resulted in the upregulation of the mTOR pathway and inhibiting the pathway may be a therapeutic agent for this subtype of leukemia.

ORGANISM(S): Mus

PROVIDER: GSE263911 | GEO | 2024/04/19

REPOSITORIES: GEO

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PLCG1 is required for AML1-ETO leukemia stem cell self-renewal

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

Paired ChIP-Seq studies of Kasumi-1 t(8;21) AML cells

Project description:Nearly 10-15% of all acute myeloid leukemia (AML) cases are caused by a recurring chromosomal translocation between 8 and 21, t(8;21). The t(8;21) translocation generates the AML1-ETO leukemia fusion protein. AML1-ETO promotes leukemogenesis by transcriptionally dysregulating important cell-fate genes. Here, to better understand how AML1-ETO deregulates transcription, we performed paired ChIP-Seq analyses of sequence-specific transcription factors, coactivators, corepressors, HDACs, RNA Pol II and acetyl-histone marks in both control and AML1-ETO-depleted Kasumi-1 t(8;21) AML cells.

2020-02-14 | GSE131939 | GEO

AML1/ETO binding pattern on human promoters

2008-12-22 | GSE10531 | GEO

Epigenetic silencing of UBXN8 contributes to leukemogenesis of t(8;21) acute myeloid leukemia

Project description:The formation of the AML1-ETO fusion protein, resulting from the t(8;21) translocation, is considered to be among the t(8;21) acute myeloid leukemia (AML) initiating events. However, the mechanisms of the oncogenic activity of AML1-ETO remains unclear. In this study, we found that AML1-ETO triggers the heterochromatic silencing of UBXN8 by recognizing the AML1 binding sites and recruiting chromatin remodeling enzymes to the UBXN8 promoter region. Decitabine, a specific inhibitor of DNA methylation, upregulated the expression of UBXN8 in AML1-ETO+ AML cell lines. Overexpression of UBXN8 inhibited the proliferation and colony-forming ability and promoted cell cycle arrest in t(8;21) AML cell lines. Enhancement of UBXN8 level can significantly inhibit the tumor proliferation of AML1-ETO+ cells in vivo. Thus, our results indicated that epigenetic silencing of UBXN8 via its promoter region methylation mediated by the AML1-ETO fusion protein contributes to the leukemogenesis of t(8;21)AML. These results demonstrated the feasibility and effectiveness of the pharmacological disruption of AML1-ETO/HDACs/DNMTs complex and that the UBXN8 targeting maybe an potential therapeutic strategy for t(8;21)AML.

2021-07-31 | GSE155466 | GEO

Genome-wide studies identify a novel interplay between AML1 and AML1/ETO in t(8;21) acute myeloid leukemia

Project description:The AML1/ETO fusion protein is essential to the development of acute myeloid leukemia (AML), and is well recognized for its dominant-negative effect on the co-existing wild-type protein AML1. However, the involvement of wild-type AML1 in AML1/ETO-driven leukemogenesis remains elusive. Through chromatin immunoprecipitation sequencing, computational analysis plus a series of experimental validations, we report here that AML1 is able to orchestrate the expression of AML1/ETO targets regardless of being activated or repressed, via forming a complex with AML1/ETO and via recruiting the cofactor. 4 ChIP-seq assays were used to identify the high confidence binding regions of AML1-ETO and AML1 in t(8;21) AML Kasumi-1 cell lines. The anti-AML1 (N20) antibody targets the N-terminus of AML1 and recognizes both AML1 and AML1/ETO; the anti-AML1 (C19) antibody targets the C-terminus of AML1 and recognizes AML1 but not AML1/ETO; the anti-ETO (C20) antibody targets the C-terminus of ETO and specifically recognizes AML1/ETO. 2 ChIP-seq assays were used to identify the binding regions of AML1 in human macrophage U937 cell lines. And the total input was used as control.

2015-11-04 | E-GEOD-65427 | biostudies-arrayexpress

Genome-wide studies identify a novel interplay between AML1 and AML1/ETO in t(8;21) acute myeloid leukemia

2015-11-04 | GSE65427 | GEO

Genes regulated by AML1/ETO in U937 cells

Project description:Approximately 20% of Acute Myelogenous Leukemia (AML) cases carry the t(8;21) translocation, which involves the AML1 and ETO genes, and express the resulting AML1/ETO fusion protein that functions as a transcriptional repressor by recruiting NCoR/SMRT/HDAC complexes to DNA. We used microarrays to identify genes differentially expressed in U937 cells expressing AML1/ETO compared to vector transfected U937 cells. Keywords: Transcriptional regulation

2008-11-28 | GSE10520 | GEO

Acute myeloid leukemia (AML) patient blasts and healthy hematopoietic stem and progenitor cell (HSPC) RNA-sequencing Data

Project description:Acute myeloid leukemia (AML) with the t(8;21)(q22;q22) chromosomal translocation is among the most common subtypes of AML and produces the AML1-ETO (AE) oncogenic fusion gene. AML1-ETO expression is critical to for t(8;21) AML leukemogenesis and maintenance. Post-transcriptional regulation of gene expression is often mediated through transcript 3'-untranslated regions (UTR). AML1-ETO uses the 3’UTR of the ETO gene, which is not normally expressed in hematopoietic cells. Therefore, the mechanisms regulating AML1-ETO via the 3’UTR are attractive therapeutic targets. In this study, we examine the regulation of AML1-ETO via the 3’UTR. We demonstrate that AML1-ETO primarily uses a 3.7kb isoform of the ETO 3’UTR in both t(8;21) patients and cell lines. Using a luciferase assay approach, we identify an AML1-ETO 3’UTR fragment between 2.8 and 3.4kb which is negatively regulated, increases expression upon inhibition of microRNA biogenesis, and contains a putative let-7 microRNA target site. We show that let-7b directly represses AML1-ETO through this site. An analysis of The Cancer Genome Atlas AML dataset shows that let-7b and let-7 family miRNA expression is significantly lower in t(8;21) AML than other AMLs. Finally, we demonstrate that let-7b-5p inhibits the proliferation of t(8;21) AML cell lines, rescues expression of AML1-ETO target genes, and promotes differentiation. Our findings establish AML1-ETO as a let-7b target gene and suggest that let-7 based therapeutics may be applied to t(8;21) AML.

2021-12-31 | GSE149237 | GEO

Epigenetic minicircuitry of AML1-ETO/THAP10/MIR383 contributes t(8;21) AML leukemogenesis

Project description:AML1-ETO is regarded as an initial event and plays a pivotal role in t(8;21) acute myeloid leukemia (AML) which is a highly heterogeneous disease. DNA methylation patterns are frequently deregulated in t(8;21) AML, though little is known of the mechanisms through which specific gene sets become aberrantly methylated. Here, We found that the promoter DNA methylation signature of t(8;21) AML blasts differs from those of normal CD34+ bone marrow cells and other AMLs. This signature contains 408 differentially methylated genes, many of which are genes involved in cancer pathway and myeloid leukemia. Database systematic survey and differential methylated regions (DMR) analysis were performed. These study demonstrated that a novel hypermethylated zinc finger containing protein-THAP10 is a target gene and can be epigenetic silenced by AML1-ETO at transcriptional level in t(8;21) AML and silencing of THAP10 by AML1-ETO predicts a poor clinical outcome. Our findings also identified that THAP10 is a bona fide target of miR-383 which can be epigenetic activated by AML1-ETO. In this study, we provided evidence that epigenetic silencing of THAP10 is the mechanistic link between AML1-ETO fusion proteins and tyrosine kinase cascades. In addition, we showed that THAP10 is a nuclear protein which inhibits myeloid proliferation inhibition and promotes differentiation both in vitro and in vivo. Altogether, our results revealed an unexpected and important link between fusion protein AML1-ETO, mir-383, THAP10 and tyrosine cascades in t(8;21) AML.

2017-04-30 | GSE80508 | GEO

Analysis of expression levels of genes on chromosome 19 in U937 cells expressing AML1/ETO

Project description:Approximately 20% of Acute Myelogenous Leukemia (AML) cases carry the t(8;21) translocation, which involves the AML1 and ETO genes, and express the resulting AML1/ETO fusion protein that functions as a transcriptional repressor by recruiting NCoR/SMRT/HDAC complexes to DNA. We used ChIP-chip to identify the determinants of AML1/ETO binding on a contiguous DNA region (chromosome 19). In order to correlate transcription factor binding to gene expression, we evaluated expression levels of genes localized on chromosome 19 by expression tiling. Keywords: Gene expression

2008-11-28 | GSE10579 | GEO

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