The biology of chronic myeloid leukemia (CML)-stem cells is still incompletely understood. Therefore, we previously developed an inducible transgenic mouse model in which stem cell targeted induction of BCR-ABL expression leads to chronic phase CML-like disease. Here, we now demonstrate that the disease is transplantable using BCR-ABL positive LSK cells (lin-Sca-1+c-kit+). Interestingly, the phenotype is enhanced when unfractionated bone marrow (BM) cells are transplanted. However, neither progenitor cells (lin-Sca-1-c-kit+) nor mature granulocytes (CD11b+Gr-1+), or potential stem cell niche cells were able to transmit the disease or alter the phenotype. The phenotype was largely independent of BCR ABL priming prior to transplant. However, BCR-ABL abrogated the potential of LSK cells to induce full blown disease in secondary recipients. Subsequently, we found that BCR-ABL increased the fraction of multipotent progenitor cells (MPP) at the expense of long term HSC (LT-HSC) in the BM. Microarray analyses of LSK cells revealed that BCR-ABL alters the expression of genes involved in proliferation, survival, and hematopoietic development. Our results suggest that BCR-ABL induces differentiation of LT-HSC and decreases their self renewal capacity. Furthermore, reversion of BCR-ABL eradicates mature cells while leukemic stem cells persist, giving rise to relapsed CML upon re-induction of BCR-ABL.
BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Increased DNA methylation of Dnmt3b targets impairs leukemogenesis.
Specimen part
View SamplesHere, we analyzed global gene expression changes that were associated with over expression of Dnmt3b in MLL-AF9 induced leukemias using the Affymetrix microarray platform.
Increased DNA methylation of Dnmt3b targets impairs leukemogenesis.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia.
Specimen part, Disease
View SamplesMicroarray gene profilling indentified snoRNAs are downstream target of Amino Enhancer of Split (AES) and are essential for AML1-ETO9a induced leukemia.
AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia.
No sample metadata fields
View SamplesSalmonella enterica serotype Typhimurium causes an acute inflammatory reaction in the cecum of streptomycin pre-treated mice. We determined global changes in gene expression elicited by serotype Typhimurium in the cecal mucosa. The gene expression profile was dominated by T cell derived cytokines and genes whose expression is known to be induced by these cytokines. Markedly increased mRNA levels of interferon (IFN-gamma), interleukin-22 (IL-22) and IL-17 were detected by quantitative real-time PCR. Furthermore, mRNA levels of genes whose expression is induced by IFN-gamma, IL-22 or IL-17, including macrophage inflammatory protein 2 (MIP-2), inducible nitric oxide synthase (Nos2), lipocalin-2, MIP-1alpha, MIP-1beta, and keratinocyte-derived cytokine (KC), were also markedly increased. To assess the importance of T cells in orchestrating this pro-inflammatory gene expression profile, we depleted T cells using a monoclonal antibody prior to investigating cecal inflammation caused by serotype Typhimurium in streptomycin pre-treated mice. Depletion of CD3+ T cells resulted in a dramatic reduction in gross pathology, a significantly reduced recruitment of neutrophils and a marked reduction in mRNA levels of IFN-gamma, IL-22, IL-17, iNOS, lipocalin-2 and KC. Our results suggest that T cells play an important role in amplifying inflammatory responses induced by serotype Typhimurium in the cecal mucosa.
T cells help to amplify inflammatory responses induced by Salmonella enterica serotype Typhimurium in the intestinal mucosa.
No sample metadata fields
View SamplesSalmonella enterica serotype Typhimurium cause a localized enteric infection in immunocompetent patients while human immunodeficiency virus (HIV)-infected patients develop a life threatening bacteremia. We used a rhesus macaque ileal loop model to study how simian immunodeficiency virus (SIV) infection triggers defects in mucosal barrier function that enhance S. Typhimurium dissemination. SIV infection resulted in significant depletion of CD4+ T cells in the intestinal mucosa. Gene expression profiling revealed a defective TH17 response (with suppression of IL-17 and IL-22 expression) and impaired homeostasis of the intestinal epithelium in SIV-infected animals during NTS infection. These findings correlated with an impaired ability of lamina propria CD4+ T cells from SIV-infected macaques to produce IL-17 upon ex vivo stimulation, while production of IFN-gamma was not affected. This cytokine imbalance in SIV-infected animals was associated with reduced expression of genes required for intestinal epithelial maintenance and repair, increased fluid secretion during NTS infection, epithelial damage and translocation of a non-invasive S. Typhimurium mutant. Although no defects in neutrophil recruitment were noted, the ileum of SIV-infected animals contained lower levels of the enzyme myeloperoxidase, which may indicate defects in neutrophil killing capacity. S. Typhimurium was recovered in markedly increased numbers from the mesenteric lymph nodes of SIV-infected macaques, illustrating the increased potential for systemic dissemination during co-infection. Our data suggest that SIV-infection causes a multi-factorial defect in mucosal barrier function that promotes bacterial dissemination.
Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut.
No sample metadata fields
View SamplesWe used the ileal loop model to assess the effects of enteric bacteria organisms on host gene expression in intestinal tissue independent of and following early SIV infection. SIV infection in the gut causes rapid and severe immune dysfunction and damage to the intestinal structure, this may alter the intimate interaction with lumenal organisms. This study was performed to determine whether early SIV infection, prior to the depletion of CD4+ T cells, can alter interaction of the host with pathogenic Salmonella serovar Typhimurium (ST) or commensal Lactobacillus plantarum (LP), and to further understand the earliest changes to the intestinal mucosa following SIV infection.
Early mucosal sensing of SIV infection by paneth cells induces IL-1β production and initiates gut epithelial disruption.
Specimen part
View SamplesAbiotic stress is a major factor for crop productivity, a problem likely to be exacerbated by climate change. Improving the tolerance to environmental stress is one of the most important goals of crop breeding programmes. While the early responses to abiotic stress in plants are well studied, plant adaptation to enduring or recurring stress conditions has received little attention. This project investigates the molecular mechanism of the maintenance of acquired thermotolerance as a model case of stress memory in Arabidopsis. Arabidopsis seedlings acquire thermotolerance through a heat treatment at sublethal temperatures. To investigate the underlying mechanisms, we are investigating changes in the transcriptome at two timepoints after a heat acclimation treatment using Arabidopsis thaliana seedlings.
Arabidopsis miR156 Regulates Tolerance to Recurring Environmental Stress through SPL Transcription Factors.
Treatment
View SamplesPlants can be primed by a stress cue to mount a faster and stronger activation of defense mechanisms upon a subsequent stress. A crucial component of such stress priming is the modified reactivation of genes upon recurring stress, a phenomenon known as transcriptional memory. The transcriptional memory in response to heat stress is not clear at the genome scale.
Distinct heat shock factors and chromatin modifications mediate the organ-autonomous transcriptional memory of heat stress.
Age, Specimen part
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