Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA349148 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4432320.fastq.gz | Fastqsanger.gz | |||
| SRR4432321.fastq.gz | Fastqsanger.gz | |||
| SRR4432322.fastq.gz | Fastqsanger.gz | |||
| SRR4432323.fastq.gz | Fastqsanger.gz |
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Project description:Gfi1b - A key player in genesis and maintenance of AML and MDS [expression microarray]
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Project description:Gfi1b - A key player in genesis and maintenance of AML and MDS
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Project description:Differentiation of hematopoietic stem cells (HSCs) is regulated by a concert of different transcription factors (TFs). A disturbed function of TFs can be the basis of (pre)malignancies such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth Factor Independence 1b (Gfi1b) is a repressing TF with a key role in quiescence of HSCs and emergence and maturation of erythrocytes and platelets. Here, we show that low expression of GFI1B in blast cells is associated with inferior prognosis of MDS and AML patients. Using mouse models with either reduced expression or conditional deletion of Gfi1b, crossed with a mouse model reflecting human MDS or AML, we demonstrate that AML development was accelerated with heterozygous loss of Gfi1b, and latency was further decreased when Gfi1b was conditionally deleted. Loss of Gfi1b significantly enhanced stemness of leukemic cells with upregulation of genes fundamentally involved in leukemia development. On a molecular level, we found that loss of Gfi1b not only increased the levels of reactive oxygen species (ROS) but also induced gene expression changes of key AML pathways such as the p38/AKT pathway. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS/AML development.
2018-03-31 | GSE88934 | GEO
Project description:Differentiation of hematopoietic stem cells (HSCs) is regulated by a concert of different transcription factors (TFs). A disturbed function of TFs can be the basis of (pre)malignancies such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth Factor Independence 1b (Gfi1b) is a repressing TF with a key role in quiescence of HSCs and emergence and maturation of erythrocytes and platelets. Here, we show that low expression of GFI1B in blast cells is associated with inferior prognosis of MDS and AML patients. Using mouse models with either reduced expression or conditional deletion of Gfi1b, crossed with a mouse model reflecting human MDS or AML, we demonstrate that AML development was accelerated with heterozygous loss of Gfi1b, and latency was further decreased when Gfi1b was conditionally deleted. Loss of Gfi1b significantly enhanced stemness of leukemic cells with upregulation of genes fundamentally involved in leukemia development. On a molecular level, we found that loss of Gfi1b not only increased the levels of reactive oxygen species (ROS) but also induced gene expression changes of key AML pathways such as the p38/AKT pathway. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS/AML development. We used microarrays to detail the effect of loss of Gfi1b expression on key AML-pathways in a mouse model system
2018-03-31 | GSE88882 | GEO
Project description:The key myeloid transcription factor (TF) CEBPA is frequently mutated in acute myeloid leukemia (AML), but the molecular ramifications of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we compared gene expression changes in human CEBPA mutant AML and in the corresponding CebpaLp30 mouse model, and identified a conserved cross-species transcriptional program. ChIP-seq revealed aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. One leukemic-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased AML survival in transplanted mice. Our data indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.
2019-08-08 | PXD011359 | Pride
Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal. All 96 bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.
2011-01-01 | E-GEOD-21261 | biostudies-arrayexpress
Project description:Aplastic anaemia (AA) is a form of bone marrow failure (BMF) resulting in significant cytopenias and may progress with clonal evolution to myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). MicroRNA expression is dysregulated in MDS/AML but there are limited studies on its role in the pathogenesis of AA. Using stored BM samples (n=81) from 2006-2019 from 52 patients, we demonstrate key differences in miRNA expression between AA patients at diagnosis and de novo MDS patients (n=21). The five most significantly upregulated miRNA in MDS patients (downregulated in AA) were miR-130a-3p, miR-221-3p, miR-126-3p, miR-27b-3p and miR-196b-5p (adj p<0.001). However, at the time of AA clonal progression to secondary MDS/AML, no significant miRNA differences were identified suggesting that the underlying mechanistic pathways are similar between AA progression to MDS/AML and de novo MDS. At diagnosis, miR-127-3p, miR-1271-5p, miR-301b-5p, miR-3934-5p and miR-4531 (adj p=0.081) were upregulated in those whose AA eventually progressed in comparison to those without eventual clonal progression. Using KEGG pathway analysis derived from miRPathDBv2.0, cytokine-cytokine receptor interaction, TGF-, MAP kinase, prolactin, Hippo, neurotrophin and FOXO signalling pathways were enriched in AA patients with clonal progression to MDS/AML; these pathways were similarly enriched in the de novo MDS cohort. These studies highlight the differing miRNA expression profiles in AA and MDS and in AA clonal evolution to MDS/AML.
2023-09-02 | GSE242216 | GEO
Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal.
2011-01-01 | GSE21261 | GEO
Project description:Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a lethal complication of cancer treatment. Although t-MDS/AML development is associated with known genotoxic exposures, its pathogenesis is not well understood and methods to predict risk of development of t-MDS/AML in individual cancer survivors are not available. We performed microarray analysis of gene expression in samples from patients who developed t-MDS/AML after autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) and controls that did not develop t-MDS/AML after aHCT. CD34+ progenitor cells from peripheral blood stem cell (PBSC) samples obtained pre-aHCT from t-MDS/AML cases and matched controls, and bone marrow (BM) samples obtained at time of development of t-MDS/AML, were studied. Significant differences in gene expression were seen in PBSC obtained pre-aHCT from patients who subsequently developed t-MDS/AML compared to controls. Genetic alterations in pre-aHCT samples were related to mitochondrial function, protein synthesis, metabolic regulation and hematopoietic regulation. Progression to overt t-MDS/AML was associated with additional alterations in DNA repair and DNA-damage checkpoint genes. Altered gene expression in PBSC samples were validated in an independent group of patients. An optimal 63-gene PBSC classifier derived from the training set accurately distinguished patients who did or did not develop t-MDS/AML in the independent test set. These results indicate that genetic programs associated with t-MDS/AML are perturbed long before disease onset, and can accurately identify those at risk of developing this complication.
2011-12-12 | GSE23025 | GEO
Project description:Microarray analysis with 40,000 cDNA gene chip arrays determined differential gene expression profiles (GEPs) in CD34+ marrow cells from myelodysplastic syndrome (MDS) patients compared to normal individuals. Using focused bioinformatics analyses, we found 1175 genes significantly differentially expressed by MDS vs Normal, requiring a minimum of 39 genes to separately classify these patients. Major GEP differences were demonstrated between Normal and MDS patients and between several MDS subgroups: (1) those whose disease remained stable (sMDS) and those who subsequently transformed (tMDS) to acute myeloid leukemia (AML); (2) between del(5q) and other MDS patients. A 6-gene ‘poor risk’ signature was defined which was associated with AML transformation and provided additive prognostic information for IPSS Intermediate-1 patients. Over-expression of genes generating ribosomal proteins and for other signaling pathways was demonstrated in the tMDS patients. Comparison of del(5q) to the remaining MDS patients showed 1924 differentially expressed genes, with under-expression of 1014 genes, 11 of which were within the 5q31-32 Commonly Deleted Region. These data demonstrated (1) GEPs distinguishing MDS patients from normal and between those with differing clinical outcomes (tMDS vs sMDS) and cytogenetics [eg, del(5q)] ; and (2) molecular criteria refining prognostic categorization and associated biologic processes in MDS. Gene expression profiles from CD34+ cells of 35 MDS subjects and 6 Normals were compared.
2009-10-31 | E-GEOD-18366 | biostudies-arrayexpress