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Mus musculus
17 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
In blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver hematopoietic stem cells (HSCs). However, its function in adult HSCs is unknown. Here, using an inducible knockout model, we found that C/EBPa deficient adult HSCs underwent a pronounced expansion with enhanced proliferation, characteristics resembling fetal liver HSCs. Consistently, transcription profiling of C/EBPa deficient HSCs revealed a gene expression program similar to fetal liver HSCs. Moreover we observed that age-specific C/EBPa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically, we identified N-Myc as a C/EBPa downstream target. C/EBPa upregulation during HSC transition from an active fetal state to a quiescent adult state was accompanied by down-regulation of N-Myc, and loss of C/EBPa resulted in de-repression of NMyc. Our data establish that C/EBPa acts as a molecular switch between fetal and adult states of HSC in part via transcriptional repression of the proto-oncogene N-Myc.
Publication Title
C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
It has long been known that leukemic cells disrupt normal patterns of blood cell formation, but little is understood about mechanisms. It has generally been assumed that normal hematopoietic stem and progenitor cells (HSPC) are simply out-competed for space by malignant cells. We designed a strategy to determine if leukemic cells alter intrinsic properties and functions of normal HSPCs. Chimeric mice were generated by transplantation of normal marrow and marrow from an inducible transgenic model of chronic myelogenous leukemia (CML). With induction of CML, the composition of the marrow changed dramatically, and normal HSPCs divided more readily and lost their ability to produce lymphocytes. In contrast, only modest changes were recorded in numbers of normal hematopoietic stem cells (HSCs). However, these stem cells were not unscathed, and had reduced reconstitution and self-renewal potential upon transplantation. Interestingly, the normal bystander cells acquired gene expression patterns resembling their neighboring malignant counterparts. This suggested that much of the leukemia signature is mediated by extrinsic factors in the environment.
Publication Title
Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 23 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines rescues AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches.
Publication Title
Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In the past decade, altered lipid metabolism has been recognized to be a property of malignant cells. In this report, we describe a novel oncogenic signaling pathway exclusively in tyrosine kinase inhibitor (TKI)-resistant epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). EGFR mediates TKI-resistance through regulation of the fatty acid synthase (FASN), and inhibition of this pathway using the FASN inhibitor Orlistat, triggers cell death and reduces tumor sizes both in culture systems and in vivo. Together, data shown here provide compelling evidence that the fatty acid metabolism pathway is a candidate target for TKI-resistant NSCLC treatment.
Publication Title
Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
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.
Publication Title
Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia.
Sample Metadata Fields
Specimen part
View Samples- Populus tremula x populus alba
- 18 Downloadable Samples
- Affymetrix Poplar Genome Array (poplar)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Expression profiling and functional analysis of Populus WRKY23 reveals a regulatory role in defense.
Sample Metadata Fields
Specimen part
View Samples- Populus tremula x populus alba
- 12 Downloadable Samples
- Affymetrix Poplar Genome Array (poplar)
Description
To investigate the function of poplar WRKY23, we generated PtWRKY23-overexpressing and -underexpressing (RNAi) plants. Transgenic plants were inoculated with Melampsora rust or mock-inoculated for assessment of rust-resistance and for gene expression profiling using the poplar Affymetrix GeneChip to study the consequences of PtWRKY23 overexpression and underexpression. Transcriptome analysis of PtWRKY23 overexpressors revealed a significant overlap with the Melampsora-infection response. Transcriptome analysis also indicated that PtWRKY23 affects redox homeostasis and cell wall-related metabolism.
Publication Title
Expression profiling and functional analysis of Populus WRKY23 reveals a regulatory role in defense.
Sample Metadata Fields
Specimen part
View Samples- Populus tremula x populus alba
- 6 Downloadable Samples
- Affymetrix Poplar Genome Array (poplar)
Description
To investigate the function of poplar WRKY23, we generated PtWRKY23-overexpressing and -underexpressing (RNAi) plants. Transgenic plants were inoculated with Melampsora rust or mock-inoculated for assessment of rust-resistance and for gene expression profiling using the poplar Affymetrix GeneChip to study the consequences of PtWRKY23 overexpression and underexpression. Transcriptome analysis of PtWRKY23 overexpressors revealed a significant overlap with the Melampsora-infection response. Transcriptome analysis also indicated that PtWRKY23 affects redox homeostasis and cell wall-related metabolism.
Publication Title
Expression profiling and functional analysis of Populus WRKY23 reveals a regulatory role in defense.
Sample Metadata Fields
Specimen part
View Samples
SRP090189- Mus musculus
- 1 Downloadable Sample
Illumina HiSeq 2000
Description
Background: In order to become functionally competent but harmless mediators of the immune system, T cells undergo a strict educational program in the thymus, where they learn to discriminate between self and non-self. This educational program is, to a large extent, mediated by medullary thymic epithelial cells (mTECs) that have a unique capacity to express, and subsequently present a large fraction of body antigens. While the scope of promiscuously expressed genes by mTECs is well established, relatively little is known about the expression of variants that are generated by co- and post-transcriptional processes. Results: Our study reveals that in comparison to other cell types, mTECs display significantly higher levels of alternative splicing, as well as A-to-I and C-to-U RNA editing, which thereby further expand the diversity of their self-antigen repertoire. Interestingly, Aire, the key mediator of mTECs promiscuous gene expression, plays a limited role in the regulation of these transcriptional processes. Conclusions: Our results highlight RNA processing as another layer by which the immune system assures a comprehensive self-representation in the thymus which is required for the establishment of self-tolerance and prevention of autoimmunity. Identification of the number of genes expressed in Aire-KO MEChi Overall design: ~100ng of total RNA was isolated by Trizol extraction from MHC-II high mTECs from a pool of 3 Aire-KO mice. Poly-A-selected transcriptome libraries were generated using the non-directionnal TruSeq V3 RNA Sample Prep Kit (without additional pre-amplification) following the manufacturer''s protocols. Enrichment of DNA fragment with adapter molecules on both ends was done using 15 cycles of PCR amplification using the Illumina PCR mix and primer cocktail. Paired-end (2 × 100 bp) sequencing was performed using the Illumina HiSeq2000 machine.
Publication Title
Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 28 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Runx3-mediated transcriptional program in cytotoxic lymphocytes.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples