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GSE23025
Homo sapiens
124 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
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.
Publication Title
Altered hematopoietic cell gene expression precedes development of therapy-related myelodysplasia/acute myeloid leukemia and identifies patients at risk.
Sample Metadata Fields
Disease, Subject
View Samples- Mus musculus
- 34 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Although cure rates for acute lymphoblastic leukemia (ALL) have increased, development of resistance to drugs and patient relapse are common. The environment in which the leukemia cells are present during the drug treatment is known to provide significant survival benefit. Here, we have modeled this process by culturing murine Bcr/Abl-positive acute lymphoblastic leukemia cells in the presence of stroma while treating them with a moderate dose of two unrelated drugs, the farnesyltransferase inhibitor lonafarnib and the tyrosine kinase inhibitor nilotinib. This results in an initial large reduction in cell viability of the culture and inhibition of cell proliferation. However, after a number of days, cell death ceases and the culture becomes drug-tolerant, enabling cell division to resume. We used gene expression profiling to analyze changes in the transcriptome of these leukemia cells over a 3-4 week period, taking samples at the start, the point at which most of the leukemia cells had been eradicated while a small percentage survived, and at the end when the cells were proliferating again.
Publication Title
Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We investigated the ability of HDAC inhibitors (HDACi) to target CML stem cells. Treatment with HDACi combined with IM effectively induced apoptosis in quiescent CML progenitors resistant to elimination by IM alone, and eliminated CML stem cells capable of engrafting immunodeficient mice. In vivo administration of HDACi with IM markedly diminished LSC in a transgenic mouse model of CML. The interaction of IM and HDACi inhibited genes regulating hematopoietic stem cell maintenance and survival. HDACi treatment represents a novel and effective strategy to target LSC in CML patients receiving tyrosine kinase inhibitors.
Publication Title
Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) can be subdivided into different categories based on genetic abnormalities.
Publication Title
Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Tyrosine kinase inhibitors (TKI) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stem cells (LSC), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity in CML LSC, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSC from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSC) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony forming ability and engraftment potential in immunodeficient mice. We found that the N-Cadherin receptor plays an important role in MSC-mediated protection of CML progenitors from TKI. N-Cadherin-mediated adhesion to MSC was associated with increased cytoplasmic N-Cadherin--catenin complex formation, as well as enhanced -catenin nuclear translocation and transcriptional activity. Increased exogenous Wnt-mediated -catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-Cadherin and the Wnt--catenin pathway in protecting CML LSC during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSC to TKI treatment, and suggest new targets for treatment designed to eradicate residual LSC in CML patients.
Publication Title
Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-β-catenin signaling.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Primary pre-B acute lymphoblastic (ALL) cells do not proliferate long-term ex vivo without the presence of stromal support. We developed and use an ex vivo co-culture model, consisting of mouse leukemic pre-B Bcr/Abl-expressing ALL cells grown with mitotically inactivated mouse embryonic fibroblasts (MEFs). This system provides a generic type of environmentally-mediated protection to the ALL cells, because when the ALL cells are treated with a moderate dose of a therapeutic drug, drug-resistant ALL cells can be recovered after a 1-2 week period of culture. Some of the factors produced by stromal cells that provide protection to ALL cells have been identified. However, it is unclear if the presence of drug-treated ALL cells affects the stromal fibroblasts. The current study was initiated to examine this using expression profiling on the irradiated MEFs.
Publication Title
Expression of cassini, a murine gamma-satellite sequence conserved in evolution, is regulated in normal and malignant hematopoietic cells.
Sample Metadata Fields
Specimen part
View Samples- Saccharomyces cerevisiae
- 47 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
Perturbation of the gated-synchrony system in yeast with phenelzine, an antidepressant drug used in the treatment of affective disorders in humans, leads to a rapid lengthening in the period of the genome-wide transcriptional oscillation. The effect is a concerted, genome-scale change in expression that is first seen in genes maximally expressed in the late-reductive phase of the cycle, doubling the length of the reductive phase within two cycles after treatment. Clustering of genes based on their temporal patterns of expression yielded just three super clusters whose trajectories through time could then be mapped into a simple 3D figure. In contrast to transcripts in the late-reductive phase, most transcripts do not show transients in expression relative to others in their temporal cluster but change their period in a concerted fashion. Mapping the trajectories of the transcripts into low-dimensional surfaces that can be represented by simple systems of differential equations provides a readily testable model of the dynamic architecture of phenotype. In this system, period doubling may be a preferred pathway for phenotypic change. As a practical matter, low-amplitude, genome-wide oscillations, a ubiquitous but often unrecognized attribute of phenotype, could be a source of seemingly intractable biological noise in microarray studies.
Publication Title
A rapid genome-scale response of the transcriptional oscillator to perturbation reveals a period-doubling path to phenotypic change.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
B cells are indispensable for humoral immunity, as they ultimately give rise to antibody-secreting plasma cells. During T cell-dependent antibody responses, naive B cells form germinal centers (GCs), a distinct histologic structure found in secondary lymphoid organs. Naive B cells become activated upon interaction with T cells and antigen presenting cells, and begin to rapidly proliferate and form the characteristic GC structure.
Publication Title
The LRF transcription factor regulates mature B cell development and the germinal center response in mice.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
miR-142 gene is specifically and abundantly expressed in hematopoietic cells. Mice that lack this miRNA gene develop immunodeficiency and display altered hematopoeisis.
Publication Title
Altered lymphopoiesis and immunodeficiency in miR-142 null mice.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Genome-wide expression differences are compared for a normal and mutant cell line.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples