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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 [CUT&RUN]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181136 | GEO | 2022/03/08

REPOSITORIES: GEO

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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 (HSC) point to shared core stemness properties. However, 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 HSC self-renewal and differentiation. Integration of protein mass spectrometry and chimeric AGO2 eCLIP-seq identify TBL1XR1 as a primary miR-130a target. TBL1XR1 loss of function phenocopies miR-130a enforced expression impairing lymphoid differentiation and expanding long-term (LT)-HSC. This post-transcriptional regulation by miR-130a is usurped in t(8;21) acute myeloid leukemia (AML), whereby reduction of miR-130a results in differentiation of leukemic cells by altering chromatin binding and composition of the AML1-ETO complex. Our study establishes that comprehensive identification of the miRNA targetome within primary cells enables discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells.

2022-03-08 | GSE180129 | GEO

Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [TBL1XR1 KD]

Project description:Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSC) point to shared core stemness properties. However, discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identified miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impaired lymphoid differentiation and expanded long-term HSC. Integration of protein mass spectrometry and chimeric AGO2 eCLIP-seq identified TBL1XR1 as a primary miR-130a target, whose loss of function phenocopied miR-130a overexpression. Moreover, we found that miR-130a is highly expressed in t(8;21) AML where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells.

2022-03-08 | GSE181139 | GEO

Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [miR130aKD_Kasumi]

Project description:Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSC) point to shared core stemness properties. However, discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identified miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impaired lymphoid differentiation and expanded long-term HSC. Integration of protein mass spectrometry and chimeric AGO2 eCLIP-seq identified TBL1XR1 as a primary miR-130a target, whose loss of function phenocopied miR-130a overexpression. Moreover, we found that miR-130a is highly expressed in t(8;21) AML where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells.

2022-03-08 | GSE181137 | GEO

Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [miR-130a OE]

Project description:Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSC) point to shared core stemness properties. However, discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identified miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impaired lymphoid differentiation and expanded long-term HSC. Integration of protein mass spectrometry and chimeric AGO2 eCLIP-seq identified TBL1XR1 as a primary miR-130a target, whose loss of function phenocopied miR-130a overexpression. Moreover, we found that miR-130a is highly expressed in t(8;21) AML where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells.

2022-03-08 | GSE181138 | GEO

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

Project description: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.

| EGAD00001008412 | EGA

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

CUT&RUN of AML1-ETO binding occupancy following miR-130a KD in Kasumi-1 cells

Project description:We performed CUT&RUN assay with control Ig , anti-Flag and anti-ETO antibodies in Flag-tag AML1-ETO Kasumi-1 cells to determine binding occupancy of AML1-ETO following miR-130a KD. Kasumi-1 cells were transduced in 3 independent replicates for control and miR-130a KD samples with lentiviruses containing GFP reporter gene. GFP+ cells were sorted 3 days post-transduction and the cells were used in the CUT&RUN assay. Three antibodies were used for each biological sample.

| EGAS00001005867 | EGA

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

Cell-intrinsic Depletion of Aml1-ETO-positive Pre-leukemic HSCs by K-Ras Activating Mutation

Project description:Somatic mutations in acute myeloid leukemia (AML) are acquired sequentially and hierarchically. First, pre-leukemic mutations, such as t(8;21) that encodes AML1-ETO, are acquired within the hematopoietic stem cell (HSC) compartment, while signaling pathway mutations, including K-RAS activating mutations, are late events acquired during transformation of leukemic progenitor cells and rarely detectable in HSCs. This raises the possibility that signaling pathway mutations are detrimental to clonal expansion of pre-leukemic HSCs. To address this hypothesis we here used conditional genetics to introduce Aml1-ETO and K-RasG12D into murine HSCs, either individually or in combination. In the absence of activated Ras, Aml1-ETO expression conferred a competitive advantage to HSCs. However, activated K-Ras had a marked detrimental effect on Aml1-ETO expressing HSCs, leading to loss of both phenotypic and functional HSCs. Cell cycle analysis revealed a loss of quiescence in HSCs co-expressing Aml1-ETO and K-RasG12D, accompanied by an enrichment in E2F and Myc target gene expression and depletion of HSC self-renewal-associated gene expression. These findings provide a mechanistic basis for the observed absence of KRAS, and potentially other, signaling mutations in the pre-malignant HSC compartment.

2019-09-01 | GSE112024 | 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

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