Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

38 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Expression data of mouse hematopoietic cells, Nr4a1/3 wild type and double mutant

ABSTRACT: We investigate the cellular and molecular mechanisms of tumor suppression by NR4A1 and NR4A3, and show a cell intrinsic essential function in maintenance of hematopoietic stem cell (HSC) homeostasis. In the absence of Nr4a1/3, HSC lost quiescence, became highly proliferative leukemia-stem cell (LSC) that transplanted AML to recipient mice. We further revealed that loss of NR4A1/3 leads to deregulated expression of the key cell cycle regulator Cdkn1c (P57), c-Myc oncogene, and glucose metabolic genes leading to enhanced aerobic glycolysis or Warburg effect in LSCs. Reintroduction of Nr4a1 in LSCs restored HSC quiescence, and reversed Nr4a1/3 deficiency induced P57 suppression and c-Myc overexpression. Collectively, we identify an essential role of Nr4a1/3 in coordinately regulating cell cycle entry and glucose metabolism to prevent uncontrolled stem cell proliferation and AML transformation. These results have major implications for designing therapeutic strategies in AML. To identify NR4A-dependent molecular signaling pathways that may control HSC homeostasis, we performed genome-wide transcript profiling of Lin-Sca1+ (LS) cells from WT and DKO mice. For Affymetrix analysis, we generated three independent pools of RNA from sorted LS cells from 10-20 WT or DKO (2- to 3-week-old) mice per sample.

ORGANISM(S): Mus musculus

SUBMITTER: Orla Conneely

PROVIDER: E-GEOD-31042 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Expression data of mouse hematopoietic cells, Nr4a1/3 wild type and double mutant

Project description:We investigate the cellular and molecular mechanisms of tumor suppression by NR4A1 and NR4A3, and show a cell intrinsic essential function in maintenance of hematopoietic stem cell (HSC) homeostasis. In the absence of Nr4a1/3, HSC lost quiescence, became highly proliferative leukemia-stem cell (LSC) that transplanted AML to recipient mice. We further revealed that loss of NR4A1/3 leads to deregulated expression of the key cell cycle regulator Cdkn1c (P57), c-Myc oncogene, and glucose metabolic genes leading to enhanced aerobic glycolysis or ‘Warburg effect’ in LSCs. Reintroduction of Nr4a1 in LSCs restored HSC quiescence, and reversed Nr4a1/3 deficiency induced P57 suppression and c-Myc overexpression. Collectively, we identify an essential role of Nr4a1/3 in coordinately regulating cell cycle entry and glucose metabolism to prevent uncontrolled stem cell proliferation and AML transformation. These results have major implications for designing therapeutic strategies in AML.

2013-12-30 | GSE31042 | GEO

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Project description:Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. We found that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification was associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cell (HSC) function and AML, such as HoxA cluster genes. In vivo, HMGN1 overexpression was linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperated with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieved the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.

2020-02-25 | PXD017054 | Pride

The important role of GPR84 in MLL leukemogenesis

Project description:Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.

2014-10-15 | E-MTAB-1932 | biostudies-arrayexpress

NR4A1 and NR4A3 Restrict HSC Proliferation via Reciprocal Regulation of C/EBPα and Inflammatory Signaling

Project description:NR4A nuclear receptors are known tumor suppressors of acute myeloid leukemia and are essential regulators of hematopoietic stem cell (HSC) quiescence. To study the transcriptional consequences of acute NR4A1/3 codepletion in HSCs, we used an Nr4a1/3 conditional knockout mouse model and performed a global transcriptome profiling using RNA-Seq in sorted HSCs four days after NR4A1/3 codepletion.

2018-01-23 | GSE100990 | GEO

Microarray data of human MLLr AML cells with or without CD93 expression

Project description:Leukemia stem cells (LSCs) share several crucial properties with hematopoietic stem cells (HSCs) including self-renewal, cell cycle quiescence, and expression of a CD34+CD38- immunophenotype, which complicates efforts to eradicate AML by therapeutically targeting LSCs without adversely affecting HSCs. Here we report that CD93, a C-type lectin transmembrane receptor, is preferentially expressed on the cell surface of LSCs compared with HSCs in the genetic subtype of AML with genomic rearrangements of the MLL gene. LSCs that selectively express CD93 are actively cycling, and highly enriched for xeno-engraftment potential, yet comprise a minor component of an otherwise quiescent CD34+CD38- compartment of human AML. Notably, CD93 is required for LSC function in MLL leukemogenesis, and is not simply a passive surface marker co-expressed on LSCs. Thus, CD93 selectively marks and essentially maintains LSCs, and identifies them as predominantly cycling, non-quiescent leukemia-initiating cells in MLL-rearranged AML.

2015-10-02 | GSE64776 | GEO

All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

Project description:Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.

2019-12-13 | GSE123255 | GEO

Expression data of mRNA/LncRNA from megakaryocytes in MLL-AF9 AML mouse versus healthy control bone marrow

Project description:Thrombocytopenia is a major and fatal complication for AML, while what happened to megakaryopoiesis and thrombopoiesis in AML remains unknown. Megakaryocytes have been recognized as essential HSC niche cells for their function to maintain HSC quiescence and support HSC regeneration. Megakaryocytes are robustly affected in AML bone marrow, while the alterations of their platelet-releasing and HSC supportive function are incompletely understood.

2020-06-25 | GSE112942 | GEO

Ferritinophagy is a Druggable Vulnerability of Quiescent Leukemic Stem Cells in Acute Myeloid Leukemia

Project description:Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Post-therapy relapse, particularly driven by leukemic stem cells (LSCs), contributes to therapeutic failure and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and identified potential vulnerabilities for therapeutic intervention. We found that quiescent AML cells, enriched for LSC functions, exhibited a distinct gene set that served as a significant prognostic factor for poor outcomes in AML patients. Furthermore, quiescent cells displayed heightened autophagic activity, with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4), for iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML.

2024-06-13 | PXD042796 | Pride

Role of c-Myc haploinsufficiency in the maintenance of HSCs

Project description:Here we report a dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/b-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. We showed that c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence, and promoting its apoptosis. We have identified Nr4a1, Nr4a2 and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2 and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediated the function of c-Myc in regulating HSC quiescence while all three genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/b-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induced a blockage of erythroid lineage differentiation through promoting expression and secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc heterozygous mice, and to significantly prolong survival of such mice. Furthermore, we showed that c-Myc mediated Apc loss-induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.

2020-08-18 | GSE156361 | GEO

CD200 expression marks leukemia stem cell (LSC) in human AML part 3

Project description:The leukemia stem cell (LSC) populations of acute myeloid leukemia (AML) exhibit phenotypic, genetic and functional heterogeneity that contribute to therapy failure and relapse. Progress towards understanding the mechanistic basis for therapy resistance in LSCs has been hampered by difficulties in isolating cell fractions that enrich for the entire heterogeneous population of LSCs within individual AML samples. We previously reported that CD200 gene expression is upregulated in LSC-containing AML fractions. We demonstrate that CD200 is present on a greater proportion of CD45dim blasts compared to more differentiated CD45high cells in AML patient samples. In 75% of AML cases examined, CD200 was expressed on 10% of CD45dim blasts; of these, CD200 identified LSCs within the blast population in 90% of samples tested in xenotransplantation assays. Notably, CD200 expression captured both CD34- and CD34- LSCs within individual AML samples. Highly purified CD45dimCD200+ LSC-containing blasts were enriched in primitive HSC/progenitor-like signatures, while CD45dimCD200- nonengrafting blasts were enriched in myeloid-like signature. Moreover, analysis of CD45dimCD200+ blasts from NPM1-mutated AMLs also demonstrated an enrichment of primitive gene expression signatures compared to unfractionated (bulk) cells.

2020-10-10 | GSE159322 | GEO

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