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2574a601-0ad8-4c99-8ae5-204af3e8a946 - samples

ABSTRACT: In this study, we identified miR-130a as a regulator of HSC self-renewal and differentiation. To characterize gene expression changes following enforced expression of miR-130a OE, we performed RNA-seq in CD34+ cord blood (CB) cells transduced with control and miR-130a OE lentiviruses. To capture miRNA targets in an unbiased, transcriptome-wide manner, we perfomed enhanced CLIPseq procol in 2 replicates of CD34+ CB cells and Kasumi-1 cell line, which represent a model system for t(8;21) AML. We chose this cell line, as we found miR-130a to be highly expressed in this AML subtype where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Chimeric Ago2 eCLIPseq in CD34+ CB cells combined with Mass Spectrometry data analysis identified TBL1XR1 as a principal target of miR-130a. To elucidate gene expression changes associated with TBL1XR1 loss of function, we performed RNA-seq in CD34+CD38- CB cells transduced with control and shRNA targeted against TBL1XR1. To determine the functional significance of high miR-130a expression levels in Kasumi-1 cells on the molecular network controlled by AML1-ETO, we performed CUT&RUN assay and RNA-seq in Kasumi-1 cells following miR-130a knock-down (KD). Collectively, our findings reveal a unique role of miR-130a in regulating normal hematopoietic stem cell self-renewal and how elevated levels of miR-130a in t(8;21) AML contribute to the leukemogenesis of this AML subtype.

PROVIDER: EGAD00001008412 | EGA |

REPOSITORIES: EGA

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Global Identification of the miR-130a targetome in human HSPC Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

Project description:Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells have firmly established the existence of shared core stemness properties. However, the discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identify miR-130a as a regulator of hematopoietic stem cell (HSC) self-renewal and lineage differentiation. Integration of mass spectrometry and chimeric AGO2 eCLIP-seq identify TBL1XR1 as a primary miR-130a target. TBL1XR1 loss of function impairs lymphoid differentiation and expands long-term (LT)-HSC. This post-transcriptional regulation by miR-130a is usurped in t(8;21) acute myeloid leukemia (AML). Reduction of miR-130a levels in t(8;21) AML cells results in altered chromatin binding and composition of the AML1-ETO complex, demonstrating that miR-130a is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that comprehensive identification of the miRNA targetome within primary tissue enables the discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells.

2024-06-22 | PXD027331 | Pride

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

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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.

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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

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

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-ETOâs 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. Examination of JMJD1C and LYL1 chromatin binding in Kasumi-1 cells, HL-60 cells, NB-4 cells and THP-1 cells, including ChIP-seqs of JMJD1C and LYL1, and input DNAs for Kasumi-1, HL-60, NB4.

2015-11-02 | E-GEOD-63484 | biostudies-arrayexpress

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]

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 | GSE63484 | GEO

AML1/ETO binding pattern on human promoters

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2008-12-22 | GSE10531 | GEO

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