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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80508 | GEO | 2017/04/30

SECONDARY ACCESSION(S): PRJNA319156

REPOSITORIES: GEO

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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

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

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

HDAC3 preferentially binds to RUNX1 in t(8;21) AML cells and collaborates with RUNX1 to repress AML1-ETO-mediated transcriptional activation

Project description:Human histone deacetylase 3 (HDAC3) plays an important role in gene transcription in diseased human cells, such as leukemia. The t(8;21) chromosomal translocation is one of the most commonly observed genetic abnormalities associated with acute myeloid leukemia. This translocation generates the AML1-ETO fusion protein between the wild-type RUNX1 transcription factor and wild-type ETO transcriptional corepressor. To better understand the role of HDAC3 in t(8;21) leukemogenesis, the human HDAC3-containing complexes were isolated from stably-transfected HeLa cells by using anti-FLAG immunoprecipitation. The resulting complexes were resolved in SDS-PAGE. The components of the complexes were identified using LC-MS/MS. We report here that the human RUNX1 transcription is a component of the HDAC3 complexes. We demonstrate that HDAC3 and RUNX1 collaboratively repress AML1-ETO-mediated transcription. These results reveal new insight into how AML1-ETO, RUNX1, and HDAC3 crosstalk to deregulate gene transcription in t(8;21) leukemia cells.

2020-02-17 | PXD017230 | Pride

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

Epigenetic regulation of the apoptosis program in t(8;21) AMLs by an AML1-ETO, ERG and RUNX1 triad

Project description:The t(8;21) acute myeloid leukemia associated oncoprotein AML1-ETO is a transcription factor that aberrantly regulates the pathways that lead to myeloid differentiation. Here, we set out to investigate the effects of AML1-ETO on gene expression and the epigenome in patient blast cells. We identify two modules, one in which AML1-ETO binds promoter regions of active genes and one represented by non-promoter binding to accessible, yet inactive chromatin regions. Using genome-wide binding analysis and mass spectrometry interaction studies we identify ERG, FLI1, TAL1 and RUNX1 as common binding factors of all AML1-ETO occupied genomic regions, while LYL1 and LMO2 show preferential binding in the context of non promoter regions. Epigenetically, reduced histone acetylation levels at non-promoter regions seems HDAC dependent, as treatment with an HDACi increases acetylation and induces cell death. Both AML1-ETO modules are represented in most aberrantly regulated pathways, including many signaling pathways, self-renewal and apoptosis. For the latter, the expression of the wild type transcription factors RUNX1 and ERG is required, as alterations in expression are associated with the onset of an apoptosis program. Interestingly, upon RUNX1 or ERG knockdown this onset seems to be dependent on increased AML1-ETO expression as combinatorial knockdown of RUNX1/AML1-ETO or ERG/AML1-ETO results in rescue from apoptosis. Together our results show that the balanced interplay of the epigenetic environment and transcription factors retains an anti apoptotic phenotype in t(8;21) AML cells.

2016-11-15 | GSE76464 | GEO

RNA expression analysis upon JMJD1C depletion

Project description:The AML1-ETO fusion protein, a transcription factor generated by the t(8;21) translocation in acute myeloid leukaemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a co-activator for AML1-ETO and is required for its transcriptional program. JMJD1C is directly recruited by AML1-ETO to its target genes and regulates their expression by maintaining low H3K9me2 levels. Analyses in JMJD1C knockout mice also establish a JMJD1C requirement for AML1-ETO’s ability to increase proliferation. We also show a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it is required for leukemic programs in different AML cell types through its association with key transcription factors.

2015-11-02 | GSE63485 | GEO

Genome-wide map of JMJD1C binding in Kasumi-1 cells [ChIP-seq]

2015-11-02 | GSE63484 | GEO

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

Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal [ChIP-Seq]

Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-alpha-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP-alpha and highlights the core targets of epigenetic reprogramming in t(8;21) AML. ChIP-sequencing and DNAse1-sequencing was used for the identification of a dynamic core transcriptional network in t(8;21) AML

2014-09-24 | E-GEOD-60130 | biostudies-arrayexpress

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