Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Ectopic MYC Expression Reprograms Epigenetic Landscapes and Transcription Factor Networks to Drive Differentiation Block and Malignant Transformation in AML [ATAC-seq]

ABSTRACT: Overexpression of MYC is a common convergent consequence of genetic driver mutations in acute myeloid leukemia (AML). However, despite extensive research, the mechanisms by which this proto-oncogene promotes leukemogenesis remain incompletely understood. Here, we developed models of deregulated MYC expression in human pluripotent stem cell (hPSC)-derived myelopoiesis. We show that MYC overexpression from the endogenous locus maintaining physiological regulation is insufficient for leukemogenesis. Rather, constitutive MYC overexpression from ectopic alleles is necessary for driving and sustaining leukemia-associated phenotypes. These phenotypes depend on the widespread disruption of epigenetic landscapes imposed by MYC overexpression, which in turn underlies a differentiation arrest and dysregulation of the BACH1 transcription factor network, identified here as a mediator of these changes. Our findings shed new light into the mechanisms underlying MYC-induced malignant transformation and leukemogenesis, suggesting novel therapeutic targets for AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293201 | GEO | 2026/03/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Ectopic MYC Expression Reprograms Epigenetic Landscapes and Transcription Factor Networks to Drive Differentiation Block and Malignant Transformation in AML [RNA-Seq]

Project description:Overexpression of MYC is a common convergent consequence of genetic driver mutations in acute myeloid leukemia (AML). However, despite extensive research, the mechanisms by which this proto-oncogene promotes leukemogenesis remain incompletely understood. Here, we developed models of deregulated MYC expression in human pluripotent stem cell (hPSC)-derived myelopoiesis. We show that MYC overexpression from the endogenous locus maintaining physiological regulation is insufficient for leukemogenesis. Rather, constitutive MYC overexpression from ectopic alleles is necessary for driving and sustaining leukemia-associated phenotypes. These phenotypes depend on the widespread disruption of epigenetic landscapes imposed by MYC overexpression, which in turn underlies a differentiation arrest and dysregulation of the BACH1 transcription factor network, identified here as a mediator of these changes. Our findings shed new light into the mechanisms underlying MYC-induced malignant transformation and leukemogenesis, suggesting novel therapeutic targets for AML.

2026-03-26 | GSE293056 | GEO

Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia

Project description:Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A associated protein 30 (SAP30) through two amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, these studies reveal the mechanisms for altered epigenetic programs in AML and provide a promising targeted therapeutic strategy against AML.

2022-11-10 | GSE181519 | GEO

Epigenetically Induced Ectopic Expression of UNCX in Acute Myeloid Leukemia Associated with Impaired Proliferation and Differentiation of Myeloid Cells

Project description:We performed gene-expression profiling (GEP) of UNCX-positive versus UNCX-negative AML patients using exon-array and gene-pathway analyses. UNCX is a homeobox gene ectopically expressed in acute myeloid leukemia (AML) patients and cell lines, whose activation is induced by epigenetic modifications. Our results showed a novel leukemogenic role of UNCX in slowing myeloid cell proliferation with a differentiation arrest in AML blasts. Accordingly, UNCX expression characterizes AML cells at early stage of differentiation, mainly M2 and M3 FAB types carrying wild-type NPM1. Overall, our findings provide new relevant insights into the role of epigenetically activated homeobox genes in leukemogenesis, defining a new subgroup of AML patients.

2016-11-01 | E-MTAB-4098 | biostudies-arrayexpress

Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

Project description:Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduced AML rate and extended survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibited AML cell survival, reduced leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. Combination of miRisten with chemotherapy further enhanced the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a new therapeutic approach for inv(16) AML.

2021-09-15 | GSE184015 | GEO

Targeting RBPMS selectively eliminates leukemia initiating cells via the USP1/m6A/FOXO1 axis

Project description:Acute myeloid leukemia (AML) is a malignant tumor with high recurrence rate and poor prognosis. RNA-binding proteins (RBPs) are essential modulators of transcription and translation played critical roles and frequently dysregulated in AML. Here we show that RBPMS (RNA binding protein with multiple splicing) which is highly expressed in AML and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS abrogates self-renewal of leukemia initiating cells (LICs) and AML development but has little effect on normal hematopoiesis. Mechanistically, RBPMS maintains the stability of the m6A reader IGF2BP3 by USP1-mediated deubiquitination, which promotes the translation of the FOXO1 mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by promoting FOXO1/ENO2/ALDOC regulated glycolysis. Overexpression of FOXO1 has been shown to rescue RBPMS inhibition-induced phenotypes in both leukemia cells and mouse models. We have also designed a specific inhibitor of RBPMS that has therapeutic effects in the AML patient derived xenograft model (PDX) model. We, therefore, we highlight RBPMS as a promising drug target for AML therapy.

2023-10-04 | GSE230646 | GEO

Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia

Project description:Mutation or epigenetic silencing of the transcription factor C/EBPa is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPa whereby its expression is inversely correlated with C/EBPa activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBPa AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPa inactivation contributes to the development of leukemias with a distinct LIC phenotype. A ChIP-seq sample of C/EBPa in Macrophages is used in this study

2014-01-08 | E-GEOD-50565 | biostudies-arrayexpress

N-Myc overexpression leads to multiple types of acute leukemia in mice [WGS]

Project description:The expression of the oncogene MYCN is upregulated in acute leukemia. However, the role of MYCN in leukemogenesis is poorly understood. We established multiple types of leukemia by retroviral overexpression of N-Myc in mice and studied the mechanism of leukemogenesis. Two types of hematopoietic stem cells and three types of hematopoietic progenitor cells highly purified from the bone marrow of adult C57BL/6 mice were transduced with N-Myc and transplanted into lethally irradiated mice. Acute leukemia developed from all these populations. Notably, not only B cell acute lymphoid leukemia, but also T cell acute lymphoid leukemia, acute myeloid leukemia, acute undifferentiated leukemia, and mixed phenotype acute leukemia developed, suggesting the multiple cells of origin, regardless types of leukemia. Moreover, leukemic stem cells were identified in Kit+Sca-1+Lin- bone marrow cells. RNA-seq data revealed the leukemia type-specific transcription profiles. Interestingly, acute undifferentiated leukemia appeared to be transcriptionally close to T cell acute lymphoid leukemia. Whole genome sequencing suggested that different types of leukemia arose associated with a large number of gene mutations induced by N-Myc overexpression but independent of retroviral integration sites. This study provides a new mouse model in which varying types of leukemia develop by only one oncogene.

2023-03-01 | GSE146331 | GEO

N-Myc overexpression leads to multiple types of acute leukemia in mice [RNA-Seq]

2023-03-01 | GSE146330 | GEO

Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (Leukemia cell lines)

Project description:We demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSC), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of Msi2 in a mouse model increases HSC cell cycle progression and cooperates with BCR-ABL1 to induce an aggressive leukemia. MSI2 is over-expressed in human myeloid leukemia, and expression levels directly correlate with decreased patient survival, thereby defining MSI2 expression as a novel prognostic marker in acute myeloid leukemia (AML). Depletion of MSI2 in human myeloid leukemia cells leads to decreased proliferation and apoptosis. These data implicate the MSI2 RNA binding protein in myeloid leukemogenesis and identify a novel potential target for therapy in AML. We transduced four human leukemia cell lines with lentiviral shRNA vectors targeting MSI2. Hybridizations of treated and control samples from each cell line were dye swap replicated

2010-07-21 | E-GEOD-22775 | biostudies-arrayexpress

Sox4 is a key oncogenic target in C/EBP? mutant Acute Myeloid Leukemia

Project description:Mutation or epigenetic silencing of the transcription factor C/EBP? is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBP? whereby its expression is inversely correlated with C/EBP? activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBP? AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBP? inactivation contributes to the development of leukemias with a distinct LIC phenotype. K/L (bi-allelic Cebpa mutations) leukemic mice and Sox4 overexprssing leukemic mice were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the C57/BL6 wild type mice.

2013-03-23 | E-GEOD-45430 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data