In order to gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathway. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or 7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with 7/del(7q) by pathways involved in cell survival, whilst patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder thereby providing new targets for therapeutic intervention.
Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells.
Specimen part, Disease
View SamplesIn order to gain insight into the poorly understood pathophysiology of the myelodysplastic syndromes (MDS), we have determined the gene expression profiles of the CD34+ cells of 55 MDS patients using the Affymetrix GeneChip U133 Plus2.0 platform
Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype.
No sample metadata fields
View SamplesEffect of mycobacterial cell wall component TDM (trehalose dimycolate) of murine macrophage gene expression.
Mycobacterial trehalose dimycolate reprograms macrophage global gene expression and activates matrix metalloproteinases.
Sex, Specimen part, Time
View SamplesThis study explores the underlying pathogenic mechanisms of congenital intrinsic obstruction of the ureteropelvic junction. A hedgehog-dependent mechanism underlying mammalin intrinsic ureteropelvic obstruction is defined. Overall design: Tissue was microdissected from the kidney-ureter junction at E13.5, one day after the onset of Ptc2-lacZ expression, from PTC-/-MM mice; 2 PTC2+ and 2 PTC2- cell populations were isolated using antibodies specific for PTC2 and FACS sorting.
Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction.
Specimen part, Cell line, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Genomic profiling of CHEK2*1100delC-mutated breast carcinomas.
Specimen part
View SamplesThe goal of this study was to analyze global gene expression in specific populations of nociceptor sensory neurons, the neurons that detect damaging/noxious stimuli.
Bacteria activate sensory neurons that modulate pain and inflammation.
Specimen part
View SamplesOne of the most common genetic alterations in acute myeloid leukemia is the internal tandem duplication (ITD) in the FLT3 receptor for cytokine FLT3 ligand (FLT3L). The constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on normal hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. We report that young pre-leukemic mice with the Flt3ITD knock-in allele manifest an expansion of all DCs including classical (cDCs) and plasmacytoid (pDCs). The expansion originated in DC progenitors, occurred in a cell-intrinsic manner and was further enhanced in Flt3ITD/ITD mice. The mutation caused the downregulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Flt3ITD mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T cells (Tregs). Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity in the absence of Tregs. Thus, the FLT3-ITD mutation directly affects DC development, thereby indirectly modulating T cell homeostasis and supporting Treg expansion. This effect of FLT3-ITD may subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner. Overall design: Sorted splenic dendritic cell subsets from either Flt3+/+ or Flt3ITD/+ mice were sequenced for mRNA profiling. For each subset per genotype contains 2-3 replicates, all from independent experiments.
Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.
Specimen part, Cell line, Subject
View SamplesExtrahepatic bile ducts were isolated from mouse pups at days 0-3 and primary cholangiocytes were isolated. Cholangiocytes were treated with DMSO, bilatresone (TOX4), betavulgarin (TOX2), and isoflavanone (TOX3), as per Lorent et al, Science Translationa Medicine 2015;286:286ra67 (Fig. 1), all in DMSO. Treatment concentrations were 2.0 micrograms/ml, for 6 hours.
Extrahepatic cholangiocyte obstruction is mediated by decreased glutathione, Wnt and Notch signaling pathways in a toxic model of biliary atresia.
Treatment
View SamplesThis study shows that the TLR4/MyD88 pathway in intestinal mesenchymal cells promotes intestinal carcinogenesis in the APCmin mouse model. Overall design: 3' RNA-Seq (QuantSeq) profiling of ColVIcre+ wt and MyD88 knockout primary mouse intestinal mesenchymal cells before and after treatment with LPS for 6 hours. 3 replicates per group.
Innate Sensing through Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis.
Specimen part, Cell line, Treatment, Subject
View SamplesLoss of CLP1 activity results in the accumulation of novel sets of small RNA fragments derived from aberrant processing of tyrosine pre-tRNA. Such tRNA fragments sensitize cells to oxidative stress-induced p53 activation and p53-dependent cell death. Overall design: 2 samples, Wt and Clp1(k/k), no replicates
CLP1 links tRNA metabolism to progressive motor-neuron loss.
Specimen part, Cell line, Subject
View Samples