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.
Expression of cassini, a murine gamma-satellite sequence conserved in evolution, is regulated in normal and malignant hematopoietic cells.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Altering TET dioxygenase levels within physiological range affects DNA methylation dynamics of HEK293 cells.
Specimen part, Cell line, Treatment
View SamplesWe compared TET1 and TET3 overexpressing cells to uninduced cells with endogenous levels of the respective transcript to determine global gene expression changes.
Altering TET dioxygenase levels within physiological range affects DNA methylation dynamics of HEK293 cells.
Specimen part, Treatment
View SamplesWe compared TET triple knockdown cells to control cells treated with non-targeting siRNAs to determine global gene expression changes.
Altering TET dioxygenase levels within physiological range affects DNA methylation dynamics of HEK293 cells.
Cell line, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice.
Sex, Age, Specimen part, Subject
View SamplesIL-6 inhibition has been unsuccessful in treating psoriasis, despite high levels of tissue and serum IL-6 in patients. Additionally, de novo psoriasis onset has been reported following IL-6 blockade in rheumatoid arthritis patients. To explore mechanisms underlying these clinical observations, we backcrossed an established psoriasiform mouse model (IL-17C+ mice) with IL-6 deficient mice (IL-17C+KO) and examined the cutaneous phenotype. IL-17C+KO mice initially exhibited decreased skin inflammation, however this decrease was transient and reversed rapidly, concomitant with increases in skin Tnf, Il36//, Il24, epigen and S100a8/a9 to levels higher than those found in IL-17C+ mice. Comparison of IL-17C+ and IL-17C+KO mouse skin transcriptomes with that of human psoriasis skin, revealed significant correlation among transcripts of psoriasis patient skin and IL-17C+KO mouse skin, and confirmed an exacerbation of the inflammatory signature in IL-17C+KO mice that aligns closely with human psoriasis. Transcriptional analyses of IL-17C+ and IL-17C+KO primary keratinocytes confirmed increased expression of proinflammatory molecules, suggesting that in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines. These preclinical findings may provide insight into why arthritis patients being treated with IL-6 inhibitors develop new onset psoriasis and why IL-6 blockade for the treatment of psoriasis has not been clinically effective.
Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice.
Sex, Age, Specimen part
View SamplesAlthough 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.
Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia.
Specimen part, Treatment, Time
View SamplesEML1 and EML3 were previously shown to be histone readers involved in plant-pathogen interactions. To learn more about the developmental function of EML1 and EML3, we generated eml1 eml3 double mutant and showed that it had specific seed developmental phenotypes, including a capability to develop seed without fertilization. Next, we analyzed the mRNA expression of genes in the eml1 eml3 double mutant and compared it to its wild type. Differentially expressed (DE) genes in the mutant were identified and compared with DE of the mutants known to be involved in regulating seed development and in fertilization-independent endosperm development. Our results suggest that some targets are shared between EML histone readers and known regulators of seed development, such as MEA. Auxin response seems to be affected in both types of mutants. However, unlike MEA, EML proteins regulate auxin responsive genes not only in the endosperm, but also in the embryo. This capability makes EML proteins very good candidates for engineering apomictic seeds. Overall design: 3 eml1,eml3 double mutant samples and 3 WT samples
Arabidopsis EMSY-like (EML) histone readers are necessary for post-fertilization seed development, but prevent fertilization-independent seed formation.
Specimen part, Subject
View SamplesMice lacking the zinc finger transcription factor Specificity protein 3 (Sp3) die prenatally in the C57Bl/6 background. To elucidate the cause of mortality we analyzed the potential role of Sp3 in embryonic heart development. Sp3 null hearts display defective looping at E10.5, and at E14.5 the Sp3 null mutants have developed a range of severe cardiac malformations. In an attempt to position Sp3 in the cardiac developmental hierarchy, we analysed the expression patterns of >15 marker genes in Sp3 null hearts. Expression of Cardiac ankyrin repeat protein (Carp) was downregulated prematurely after E12.5, while expression of the other marker genes was not affected. ChIP analysis revealed that Sp3 is bound to the Carp promoter region in vivo. Microarray analysis indicates that small molecule metabolism and cell-cell interactions are the most significantly affected biological processes in E12.5 Sp3 null myocardium. Since the epicardium showed distension from the myocardium, we studied expression of Wt1, a marker for epicardial cells. Wt1 expression was diminished in epicardium-derived cells in the myocardium of Sp3 null hearts. We conclude that Sp3 is required for normal cardiac development, and suggest that it has a crucial role in myocardial differentiation. (
Transcription factor Sp3 knockout mice display serious cardiac malformations.
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View SamplesThe transcriptomes of four subpopulations of beta cells isolated by FACS from five healthy human donors. Populations were defined using cell surface-labeling antibodies, avoiding the need for fixation. Overall design: There are 5 biological replicates of 4 different cell types. Each donor yielded all 4 subtypes.
Human islets contain four distinct subtypes of β cells.
Specimen part, Subject
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