Targeted RNA-Seq of Human Naïve CD4+ cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE112706 | GEO | 2018/04/05
REPOSITORIES: GEO
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Project description:Purpose: The purpose of this RNA-seq experiment was to perform a correlation analysis of mRNA expression levels in naïve CD4+ T cells and LPS-stimulated monocytes from patients with an IKZF1 mutant haploinsufficient phenotype (H167R-a and H167R-b are two siblings carrying IKZF1 p.H167R mutation) versus patients with an IKZF1 mutant dominant negative phenotype (C1, G1) along with five healthy normal controls (HC).
2018-04-05 | GSE112707 | GEO
Project description:The complex milieu of inflammatory mediators associated with many diseases is often too dilute to directly measure in the periphery, necessitating development of more sensitive measurements suitable for mechanistic studies, earlier diagnosis, guiding selection of therapy, and monitoring interventions. Previously, we determined that plasma of recent-onset (RO) Type 1 diabetes (T1D) patients induce a proinflammatory transcriptional signature in fresh peripheral blood mononuclear cells (PBMC) relative to that of unrelated healthy controls (HC). Here, using an optimized cryopreserved PBMC-based protocol, we analyzed larger RO T1D, HC, and healthy T1D sibling cohorts. In addition, we examined T1D progression by looking at longitudinal samples. UPN727 cells were stimulated with Auto-antibody-negative (AA-) High HLA Risk Siblings plasma (n=30), Auto-antibody-negative (AA-) Low HLA Risk Siblings plasma (n=42), Recent onset T1DM plasma cultured with IL1RA (n=42), or longitudinal series plasma on T1DM progressor (n=27 chips, 5 series), on auto-antibody-positive (AA+) High HLA Risk Siblings (n=54 chips, 9 series), on auto-antibody-negative (AA-) High HLA Risk Siblings (n=60 chips, 12 series), on auto-antibody-negative (AA-) Low HLA Risk Siblings (n=31 chips, 6 series). Gene expression analysis was perfromed in order to evaluate the transcriptional signature associated with T1D.
2014-05-13 | E-GEOD-52724 | biostudies-arrayexpress
Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations were associated with acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Rexinoid receptor agonists reversed this phenotype, in part by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing a new therapeutic option in IKZF1-mutated ALL. Significance: The outcome of therapy for high-risk acute lymphoblastic leukemia remains suboptimal despite contemporary chemotherapy and the advent of targeted therapeutic approaches. Recent genomic studies have identified deletions or mutations of IKZF1 as a hallmark of high-risk ALL, but an understanding of how IKZF1 alteration contribute to leukemia development are lacking. Here we show that IKZF1 alterations drive lymphoid lineage, a stem cell-like phenotype, abnormal bone marrow adhesion, and poor responsiveness to tyrosine kinase inhibitor (TKI) therapy. Using a high-content screen, we show that retinoids reverse this phenotype in part by inducing expression of wild type IKZF1, and increase responsiveness to TKIs. These findings provide new insight into the pathogenesis of high-risk ALL and potential new therapeutic approaches. Pre-B mRNA profiles of p185 MIG and IK6 cells, DMSO or drug treated, in 3 or 4 replicates, using Illumina HiSeq 2500.
2015-09-04 | E-GEOD-68391 | biostudies-arrayexpress
Project description:Transcriptional profiling of hdac1 mutant zebrafish in comparison to their sibling embryos. Embryos resulting from a cross between heterozygous hdac1 mutant zebrafish (hi1618/+) where cultured together then mutants separated from the siblings one the basis of phenotype and RNA extracted from the two groups at 27hpf was compared in a two-colour hybridisation.
2011-01-21 | GSE26707 | GEO
Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations were associated with acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Rexinoid receptor agonists reversed this phenotype, in part by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing a new therapeutic option in IKZF1-mutated ALL. Significance: The outcome of therapy for high-risk acute lymphoblastic leukemia remains suboptimal despite contemporary chemotherapy and the advent of targeted therapeutic approaches. Recent genomic studies have identified deletions or mutations of IKZF1 as a hallmark of high-risk ALL, but an understanding of how IKZF1 alteration contribute to leukemia development are lacking. Here we show that IKZF1 alterations drive lymphoid lineage, a stem cell-like phenotype, abnormal bone marrow adhesion, and poor responsiveness to tyrosine kinase inhibitor (TKI) therapy. Using a high-content screen, we show that retinoids reverse this phenotype in part by inducing expression of wild type IKZF1, and increase responsiveness to TKIs. These findings provide new insight into the pathogenesis of high-risk ALL and potential new therapeutic approaches.
2015-09-04 | GSE54821 | GEO
Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations were associated with acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Rexinoid receptor agonists reversed this phenotype, in part by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing a new therapeutic option in IKZF1-mutated ALL. Significance: The outcome of therapy for high-risk acute lymphoblastic leukemia remains suboptimal despite contemporary chemotherapy and the advent of targeted therapeutic approaches. Recent genomic studies have identified deletions or mutations of IKZF1 as a hallmark of high-risk ALL, but an understanding of how IKZF1 alteration contribute to leukemia development are lacking. Here we show that IKZF1 alterations drive lymphoid lineage, a stem cell-like phenotype, abnormal bone marrow adhesion, and poor responsiveness to tyrosine kinase inhibitor (TKI) therapy. Using a high-content screen, we show that retinoids reverse this phenotype in part by inducing expression of wild type IKZF1, and increase responsiveness to TKIs. These findings provide new insight into the pathogenesis of high-risk ALL and potential new therapeutic approaches.
2015-09-04 | GSE68391 | GEO
Project description:Objective: Conflicting evidence exists regarding the suppressive capacity of Tregs from the peripheral blood (PB) of patients with rheumatoid arthritis (RA). Our aim was to determine whether Tregs are intrinsically defective in RA using a wide range of read-out assays. Methods: CD3+CD4+CD25+CD127low Tregs from CD45RO+ and CD45RA+ compartments of PB from patients with RA and healthy controls (HC) were analysed for phenotype, cytokine expression profile (ex vivo and after in vitro stimulation), suppression of effector T-cell proliferation and cytokine production, suppression of monocyte-derived cytokine/chemokine production, and gene expression profiling. Results: No differences were observed between patients with RA and HC regarding Treg frequency, ex vivo phenotype (CD4, CD25, CD127, CD39, CD161) or pro-inflammatory cytokine profile (IL-17, IFN-gamma, TNF-alpha). FOXP3 expression was increased in Tregs from RA blood. The ability of Tregs to suppress T-cell proliferation or cytokine (IFN-gamma, TNF-alpha) production upon co-culture with autologous CD45RO+ effector T-cells and monocytes was not significantly different between patients with RA and HC. CD45RO+ Tregs from RA blood showed a slightly impaired ability to suppress production of some cytokines/chemokines by autologous LPS-activated monocytes (IL-1-beta, IL-1Ra, IL-7, CCL3, CCL4), but this was not true for all patients and other cytokines/chemokines (TNF-alpha, IL-6, IL-8, IL-12, IL-15, CCL5) were suppressed in the majority of patients similarly to HC. Finally, gene expression profiling of CD45RA+ or CD45RO+ Tregs from PB revealed no statistically significant differences between patients with RA and HC. Conclusions: Our findings suggest that Tregs isolated from PB of patients with RA are not intrinsically defective.
2015-09-05 | GSE65010 | GEO
Project description:We studied a cohort of 221 high-risk pediatric B-progenitor ALL patients that excluded known high risk ALL subtypes (BCR-ABL1 and infant ALL), using Affymetrix single nucleotide polymorphism microarrays, gene expression profiling and candidate gene resequencing. A CNA poor outcome predictor was identified using a semi-supervised principal components approach, and tested in an independent validation cohort of 258 pediatric B-progenitor ALL cases. Over 50 regions of recurring somatically acquired CNA, with the most frequently targeted genes encoding regulators of B-lymphoid development (66.8% of cases; with PAX5 targeted in 31.7% and IKZF1 in 28.6%). A CNA classifier identified a very poor outcome subgroup in the high-risk cohort (P=4.2x10-5) and was strongly associated with the presence of deletions involving IKZF1, which encodes the early lymphoid transcription factor IKAROS. This classifier, and IKZF1 deletions, also predicted poor outcome and elevated minimal residual disease at the end of induction therapy in the validation cohort. The gene expression signature of the poor outcome group was characterized by reduced expression of B lineage specific genes, and was highly related to the expressing signature of BCR-ABL1 ALL, a known high-risk ALL subtype also characterized by a high frequency of IKZF1 deletion.Somatically acquired deletions involving IKZF1 identify a very poor outcome subgroup of pediatric ALL patients. Incorporation of molecular tests to identify IKZF1 deletion in diagnostic leukemic blasts should improve the ability to accurately risk stratify patients for appropriate therapy. Affymetrix U133A arrays were performed according to the maufacturers directions on RNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples. Samples with less than 80% blasts were flow sorted prior to RNA extraction Experiment Overall Design: One hundred seventy five pediatric B-progenitor ALL samples were studied using either Affymetrix U133A
2008-10-26 | E-GEOD-12995 | biostudies-arrayexpress
Project description:Deletions within the human IKZF1 gene, which encodes Ikaros, a zinc finger transcription factor critical for lymphopoiesis, appear to be the most prominent recurring lesion in human BCR-ABL1+ (Ph+) B-ALL. Furthermore, IKZF1 mutations correlate with poor prognosis of progenitor B-ALL, further strengthening the notion that IKZF1 is a critical tumor suppressor gene in human B-lineage malignancies. To better understand the relationship between Ikzf1 mutations, BCR-ABL, and B-lineage leukemia, we examined the effect of two newly generated Ikzf1 germline mutation on BCR-ABL-induced proliferation and leukemogenesis in vitro and in vivo. We recently showed that deletion of either the exon encoding the first or the fourth DNA-binding zinc finger of Ikaros (IkZnF1-/- and IkZnF4-/-) led to distinct defects in lymphoid development and tumor suppression with de-regulation of distinct subsets of genes, providing a powerful tool for elucidation of Ikaros target genes and mechanism of function. Importantly, IkZnF4-/- had lost Ikaros tumor suppression function, while not abolishing B-cell development. Retroviral expression of BCR-ABL1 p185 in bone marrow cells from the two Ikzf1 mutant strains demonstrated that loss of ZnF4 resulted in expansion of progenitor B cells, with enhanced proliferation in vitro and a less mature cell surface B-cell phenotype in comparison to transduced wild-type bone marrow. Furthermore, in an in vivo model of BCR-ABL+ B-ALL, leukemias generated in the IkZnF4-/- background were more aggressive than those observed in a wild-type background, with cell phenotype corresponding to the in vitro cell cultures. Genome wide high throughput expression analysis (RNA-Seq) revealed a distinct subset of deregulated genes in the IkZnF4-/- BCR-ABL+ in vitro cell cultures, and molecular analysis demonstrated that this in vitro system is amendable for functional studies. These results establish a mouse model for studying the role of Ikzf1 mutations in B-ALL, and for understanding how BCR-ABL collaborates with Ikzf1 mutations to generate aggressive B-ALL.
2017-02-06 | GSE39160 | GEO
Project description:Hydrogen cyanide (HCN) is coproduced with ethylene in plant cells and primarily enzymatically detoxified by the mitochondrial ß-cyanoalanine synthase (CAS-C1). Permanent or transient depletion of CAS-C1 activity in Arabidopsis results in physiological alterations in the plant that suggest that the function of HCN is a gasotransmitter molecule. Label-free quantitative proteomic analysis of enriched mitochondrial samples isolated from the wild type and cas-c1 mutant revealed significant changes in protein content, identifying 451 proteins that are absent or less abundant in cas-c1 and 353 proteins that are only present or more abundant in the mutant background. Gene ontology classification of these proteins highlights proteomic changes that explains the root hairless phenotype and the altered immune response observed in the cas-c1 mutant. The mechanism of action of cyanide as a signaling molecule has been addressed using two proteomic approaches focused on identifying the S-cyanylation of cysteine as a posttranslational modification of proteins. Both the 2-imino-thiazolidine chemical method and the direct untargeted analysis of proteins using LC-MS/MS identified a set of 163 proteins susceptible to S-cyanylation that included sedoheptulose 1, 7-bisphosphatase (SBPase), the peptidyl-prolyl cis-trans isomerase (CYP20-3) and enolase 2 (ENO2). In vitro analysis of these proteins identified that this modification in the SBPase Cys74, CYP20-3 Cys259 and ENO2 Cys346 residues affected the enzymatic activity of the enzymes. GO classification and protein-protein interaction cluster analysis revealed the function of S-cyanylation in the regulation of primary metabolic pathways, such as glycolysis, and the Calvin and S-adenosylmethionine cycles.
2019-01-09 | PXD009929 | Pride