AML1-ETO-induced FOXO1 activates a self-renewal program in pre-leukemia stem cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE80773 | GEO | 2017/10/30
SECONDARY ACCESSION(S): PRJNA319962
REPOSITORIES: GEO
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Project description:High-resolution proteomic analysis of acute myeloid leukemia (AML) stem cells identified phospholipase C- and Ca++-signaling pathways to be differentially regulated in AML1-ETO (AE) driven leukemia. Phospholipase C gamma 1 (Plcg1) could be identified as a direct target of the AE fusion. Genetic Plcg1 inactivation abrogated disease initiation by AE, reduced intracellular Ca++-release and inhibited AE-driven self-renewal programs. In AE-induced leukemia, Plcg1 deletion significantly reduced disease penetrance, number of leukemia stem cells and abrogated leukemia development in secondary recipient hosts. In human AE-positive leukemic cells inactivation of Plcg1 reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for maintenance of murine and human hematopoietic stem- and progenitor cells (HSPCs). Pharmacologic inhibition of Ca++-signaling downstream of Plcg1 resulted in impaired proliferation and self-renewal capacity in AE-driven AML. Thus, the Plcg1 pathway represents a novel specific vulnerability of AE-driven leukemia and poses an important new therapeutic target.
2022-01-12 | PXD011251 | Pride
Project description:Leukemia stem cells are characterized by aberrant self-renewal capacity. Targeting oncogenic fusions that mediate this aberrant self-renewal capacity remains a therapeutic challenge. The t(8;21) translocation, resulting in the oncogenic fusion AML1-ETO (AE, RUNX1-RUNXT1) is among the most common chromosomal rearrangements found in acute myeloid leukemia (AML). By conducting high-resolution proteomic analysis on myeloid leukemia stem cells we identified Phospholipase C- and Ca++-signaling pathways to be differentially regulated in AE/t(8;21) AML. Phospholipase C gamma 1 (Plcg1) was specifically, and highly expressed in t(8;21) AML and could be identified as a direct target of the AML1(RUNX1)-ETO fusion. Genetic inactivation of Plcg1 resulted in abrogation of disease initiation by AE, reduction of intracellular Ca++ release and loss of AE-driven self-renewal programs. Plcg1 deletion after onset of AE-induced leukemia significantly reduced disease penetrance, number of leukemia stem cells and resulted in abrogation of leukemia development in secondary recipients. Inactivation of Plcg1 in human AE-positive AML cells by RNAi reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for steady state hematopoiesis and maintenance of murine and human hematopoietic stem cells (HSC). Translationally, we used pharmacologic inhibition of Ca++ signaling downstream of Plcg1 in AE-driven AML and this resulted in impaired proliferation and self-renewal capacity. The Plcg1 pathway represents a novel, specific vulnerability of AE-driven leukemia and represents an important new therapeutic target.
2019-09-02 | GSE122062 | GEO
Project description:Leukemia stem cells are characterized by aberrant self-renewal capacity. Targeting oncogenic fusions that mediate this aberrant self-renewal capacity remains a therapeutic challenge. The t(8;21) translocation, resulting in the oncogenic fusion AML1-ETO (AE, RUNX1-RUNXT1) is among the most common chromosomal rearrangements found in acute myeloid leukemia (AML). By conducting high-resolution proteomic analysis on myeloid leukemia stem cells we identified Phospholipase C- and Ca++-signaling pathways to be differentially regulated in AE/t(8;21) AML. Phospholipase C gamma 1 (Plcg1) was specifically, and highly expressed in t(8;21) AML and could be identified as a direct target of the AML1(RUNX1)-ETO fusion. Genetic inactivation of Plcg1 resulted in abrogation of disease initiation by AE, reduction of intracellular Ca++ release and loss of AE-driven self-renewal programs. Plcg1 deletion after onset of AE-induced leukemia significantly reduced disease penetrance, number of leukemia stem cells and resulted in abrogation of leukemia development in secondary recipients. Inactivation of Plcg1 in human AE-positive AML cells by RNAi reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for steady state hematopoiesis and maintenance of murine and human hematopoietic stem cells (HSC). Translationally, we used pharmacologic inhibition of Ca++ signaling downstream of Plcg1 in AE-driven AML and this resulted in impaired proliferation and self-renewal capacity. The Plcg1 pathway represents a novel, specific vulnerability of AE-driven leukemia and represents an important new therapeutic target.
2022-05-02 | GSE120828 | GEO
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
Project description:T(8;21), which produces the AML1-ETO (AE) fusion oncoprotein, is one of the most common chromosomal abnormalities in AML patients. Despite its prevalence among patients, it has remained challenging to study the impact of AE on leukemia development in vivo due to limitations of the current t(8;21) mouse models. Here, we devised a germline transmitted transgenic Rosa26-AE9a knock-in mouse model that expresses AE9a protein, a truncated AE variant, at moderately elevated levels compared to endogenous RUNX1. These mice develop myeloid leukemia with longer latency and lower penetrance compared to mice using the AE9a retroviral transduction-transplantation model. Pre-leukemic mice exhibited myeloid progenitor skewing in their bone marrow, with more granulocyte-monocyte progenitors (GMP) at the expense of megakaryocyte-erythroid progenitors (MEP). Importantly, hematopoietic stem and progenitor cells (HSPCs) of pre-leukemic mice had increased clonogenic potential. We performed single cell RNA-sequencing on pre-leukemic HSPCs and confirmed both this granulocytic bias and hindered differentiation. Overall, we have overcome the limitation of uncontrolled AE9a oncogene expression in the retroviral transduction-transplantation mouse model and have devised a new germline transmitted Rosa26 locus AE9a knock-in model that more faithfully represents t(8;21) human disease.
2023-10-11 | GSE173712 | GEO
Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. This SuperSeries is composed of the following subset Series: GSE29222: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [ChIP-Seq and DNAse-Hypersensitivity data] GSE29223: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [expression array data] GSE34540: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (ChIP-seq) GSE34594: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (Illumina expression) Refer to individual Series
2012-03-26 | E-GEOD-29225 | biostudies-arrayexpress
Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. 14 samples include: RUNX1 Kasumi-1, RUNX1/ETO control, RUNX1/ETO siMM, RUNX1/ETO siRE, RUNX1_non-t(8;21), H3K9Ac_siMM, H3K9Ac_siRE, POLII_siMM and POLII_siRE ChIP-Seq samples, and Kasumi-1, non-t(8;21), t(8;21) paitent#1, t(8;21) paitent#2 and CD34 normal DNasel HS samples.
2012-03-27 | E-GEOD-29222 | biostudies-arrayexpress
Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. RUNX1 siMM and RUNX1 siRE ChIP-Seq samples and a paired-end ChIP-Seq samples from patients with t(8;21) AML are used in this study; there are two paired-end ChIP-Seq runs and control per patient
2012-03-27 | E-GEOD-34540 | biostudies-arrayexpress
Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. Total RNA were obtained using 8 samples over four time courses (mismatch control and knock-down)
2012-03-27 | E-GEOD-29223 | biostudies-arrayexpress
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