Sickle cell disease (SCD) is caused by a pathogenic hemoglobin (Hb) mutation, yet patients can have dramatically variable clinical manifestations. Here we address the genetic basis of this clinical heterogeneity. Using a systems genetics approach, we performed whole blood gene expression analysis and eQTL analysis on different clinical phenotypes in SCD patients.
Genomic architecture of sickle cell disease in West African children.
Sex, Age
View SamplesImatinib has become the current standard therapy for patients with chronic myelogenous leukaemia (CML). For a better understanding of the Imatinib-related molecular effects in vivo, we assessed gene expression profiles of Philadelphia Chromosome positive (Ph+) CD34+ cells from peripheral blood of 6 patients with de novo CML in chronic phase. After 7 days of treatment with Imatinib the Ph+ CD34+ cells were reassessed to look for changes in the transcriptome. The expression level of 303 genes was significantly different comparing the transcriptome of the Ph+ CD34+ cells before and after 7 days of Imatinib therapy (183 down-regulated, 120 up-regulated, lower bound 1.2-fold). For a substantial number of genes governing cell cycle and DNA replication, the level of expression significantly decreased (CDC2, RRM2, PCNA, MCM4). On the other hand, therapy with Imatinib was associated with an increase of genes related to adhesive interactions, such as L-selectin or CD44. A group of 8 genes with differential expression levels were confirmed using a gene specific quantitative real-time PCR. Thus, during the first week of treatment, Imatinib is preferentially counteracting the bcr-abl induced effects related to a disturbed cell cycle and defective adhesion of leukemic Ph+ CD34+ cells.
Early in vivo changes of the transcriptome in Philadelphia chromosome-positive CD34+ cells from patients with chronic myelogenous leukaemia following imatinib therapy.
No sample metadata fields
View SamplesMicroarray used to detail bulk transcriptomic differences between sorted CD4+CD25+CD127lo/- Treg and CD4+CD25-CD127+ Tconv from adult peripheral blood (APB) and cord blood (CB) after a 14 day expansion period.
Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood.
Specimen part
View SamplesWe found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors.
The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy.
Specimen part
View SamplesGenome-wide transcriptional profiling of purified telomerase deficient (Terc-/-) and WT LSCs was performed in order to gain insights into the mechanisms underlying the susceptibilities of Terc-/- LSCs in vivo.
Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy.
Specimen part
View SamplesRegulatory T cells (Tregs) are a barrier to effective anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune homeostasis, Treg-restricted Nrp1 deletion in mice results in profound tumor resistant due to Treg functional fragility. Drivers of Treg fragility, the mechanistic basis of Nrp1 dependency, and the relevance of these processes for human cancer and immunotherapy remain unknown. NRP1 expression on human Tregs in melanoma and HNSCC was highly heterogeneous and correlated with prognosis. Using a mouse model of melanoma in which mutant Nrp1-deficient (Nrp1–/–) and wild type (WT) Tregs could be assessed in a competitive environment, we found that a high proportion of intratumoral Nrp1–/– Tregs produce interferon-? (IFN?), which in turn drove the fragility of surrounding WT Tregs, boosting anti-tumor immunity and facilitating tumor clearance. We also show that IFN?-induced Treg fragility is required for an effective response to PD1 immunotherapy, suggesting that cancer therapies promoting Treg fragility may be efficacious . Overall design: Tregs from B16 tumors and non-draining lymph nodes NDLN from WT, Nrp-1 deficient homozygous and heterozygous mice
Interferon-γ Drives T<sub>reg</sub> Fragility to Promote Anti-tumor Immunity.
Specimen part, Subject
View SamplesThe objective of this study is to create an encyclopedia of all genes expressed in the glomerular endothelial cell under normal and diabetic conditions. We utilized Tie2-GFP transgenic mice to mark cells of the glomerular endothelium. To induce diabetic nephropathy (DB), a genetic model of DB, BKS.Cg-m +/+ Leprdb/J from Jax laboratories was used. We utilized fluorescent activated cell sorting (FACS) to isolate glomerular endothelial cells from normal and diabetic mice. The RNAs from these samples were isolated and utilized to hybridize to microarrays, which offers a powerful, efficient and effective method for the creation of a gene expression atlas.
Gene expression programs of mouse endothelial cells in kidney development and disease.
Age, Specimen part
View SamplesThe long term objective is to create an encyclopedia of the expression levels of all genes in multiple components of the developing kidney. The central thesis is straightforward. The combination of fluorescent activated cell sorting (FACS) plus microarray analysis offers a powerful, efficient and effective method for the creation of a global gene expression atlas of the developing kidney. Microarrays with essentially complete genome coverage can be used to quantitate expression levels of every gene in FACS isolated components of the developing kidney. The ensuing rapid read-out provides an expression atlas that is more sensitive, more economical and more complete than would be possible by in situ hybridizations alone.
Gene expression programs of mouse endothelial cells in kidney development and disease.
Sex
View SamplesThe long term objective is to create an encyclopedia of the expression levels of all genes in multiple components of the developing kidney. The central thesis is straightforward. The combination of fluorescent activated cell sorting (FACS) plus microarray analysis offers a powerful, efficient and effective method for the creation of a global gene expression atlas of the developing kidney. Microarrays with essentially complete genome coverage can be used to quantitate expression levels of every gene in FACS isolated components of the developing kidney. The ensuing rapid read-out provides an expression atlas that is more sensitive, more economical and more complete than would be possible by in situ hybridizations alone.
Gene expression programs of mouse endothelial cells in kidney development and disease.
No sample metadata fields
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