Whole-exome sequencing of acute erythroid leukemia
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ABSTRACT:
PROVIDER: EGAS00001003696 | EGA |
REPOSITORIES: EGA
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Project description:Background: It has been reported that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway regulates erythropoietin (EPO)-induced survival, proliferation, and maturation of early erythroid progenitors. Erythroid cell proliferation and survival has also been related to activation of the JAK-STAT pathway. The goal of this study was to observe the function of EPO activation of JAK-STAT and PI3K/AKT pathways in the development of erythroid progenitors from hematopoietic CD34+ progenitor cells, as well as to distinguish early EPO target genes in human erythroid progenitors during ontogeny. Methods: Hematopoietic CD34+ progenitor cells, isolated from fetal and adult hematopoietic tissues, were differentiated into erythroid progenitor cells. We have used microarray analysis to examine JAK-STAT and PI3K/AKT related genes, as well as broad gene expression modulation in these human erythroid progenitor cells. Results: In microarray studies, a total of 1755 genes were expressed in fetal liver, 3844 in cord blood, 1770 in adult bone marrow, and 1325 genes in peripheral blood-derived erythroid progenitor cells. The erythroid progenitor cells shared 1011 common genes. Using the Ingenuity Pathways Analysis software, we evaluated the network pathways of genes linked to hematological system development, cellular growth and proliferation. The KITLG, EPO, GATA1, PIM1 and STAT3 genes represent the major connection points in the hematological system development linked genes. Some JAK-STAT signaling pathway-linked genes were steadily upregulated throughout ontogeny (PIM1, SOCS, MYC, PTPN11), while others were downregulated (PTPN6, PIAS, SPRED2). In addition, some JAK-STAT pathway related genes have specific expression just at certain stages of ontogeny (STATs, GRB2, CREBB). Beside continuously upregulated (AKT1, PPP2CA, CHUK, NFKB1) and downregulated (FOXO1, PDPK1, PIK3CG) genes in the PI3K-AKT signaling pathway, we also observed intermittently regulated gene expression (NFKBIA, YWHAH). Conclusions: This broad overview of gene expression in erythropoiesis revealed transcription factors with a prevalence at certain stages of ontogenesis. Finally, our results show that EPO-mediated proliferation and survival of erythroid progenitors occurs mainly through modulation of JAK-STAT pathway associated STATs, GRB2 and PIK3 genes, as well as AKT pathway- coupled NFKBIA and YWHAH genes.
2012-06-01 | GSE37869 | GEO
Project description:Background: It has been reported that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway regulates erythropoietin (EPO)-induced survival, proliferation, and maturation of early erythroid progenitors. Erythroid cell proliferation and survival has also been related to activation of the JAK-STAT pathway. The goal of this study was to observe the function of EPO activation of JAK-STAT and PI3K/AKT pathways in the development of erythroid progenitors from hematopoietic CD34+ progenitor cells, as well as to distinguish early EPO target genes in human erythroid progenitors during ontogeny. Methods: Hematopoietic CD34+ progenitor cells, isolated from fetal and adult hematopoietic tissues, were differentiated into erythroid progenitor cells. We have used microarray analysis to examine JAK-STAT and PI3K/AKT related genes, as well as broad gene expression modulation in these human erythroid progenitor cells. Results: In microarray studies, a total of 1755 genes were expressed in fetal liver, 3844 in cord blood, 1770 in adult bone marrow, and 1325 genes in peripheral blood-derived erythroid progenitor cells. The erythroid progenitor cells shared 1011 common genes. Using the Ingenuity Pathways Analysis software, we evaluated the network pathways of genes linked to hematological system development, cellular growth and proliferation. The KITLG, EPO, GATA1, PIM1 and STAT3 genes represent the major connection points in the hematological system development linked genes. Some JAK-STAT signaling pathway-linked genes were steadily upregulated throughout ontogeny (PIM1, SOCS, MYC, PTPN11), while others were downregulated (PTPN6, PIAS, SPRED2). In addition, some JAK-STAT pathway related genes have specific expression just at certain stages of ontogeny (STATs, GRB2, CREBB). Beside continuously upregulated (AKT1, PPP2CA, CHUK, NFKB1) and downregulated (FOXO1, PDPK1, PIK3CG) genes in the PI3K-AKT signaling pathway, we also observed intermittently regulated gene expression (NFKBIA, YWHAH). Conclusions: This broad overview of gene expression in erythropoiesis revealed transcription factors with a prevalence at certain stages of ontogenesis. Finally, our results show that EPO-mediated proliferation and survival of erythroid progenitors occurs mainly through modulation of JAK-STAT pathway associated STATs, GRB2 and PIK3 genes, as well as AKT pathway- coupled NFKBIA and YWHAH genes. Adult peripheral blood mononuclear cells were isolated from buffy coats of 3 healthy donors using Lymphocyte Separation Medium (BioWhittaker, Walkersville, MD). We washed mononuclear cells twice with Dulbecco's phosphate-buffered saline (PBS, Invitrogen Corporation, Carlsbad, CA), and CD34+ cells were purified by positive immunomagnetic selection using the MACS cell isolation system (Miltenyi Biotec, Auburn, CA). Fresh bone marrow CD34+ cells were collected (AllCells LLC, Berkeley, CA). Cord blood CD34+ cells (AllCells LLC) and fetal liver CD34+ cells (Cambrex Bio Science, Inc., Walkersville, MD) were collected and frozen. For analysis, CD34+ cells were resuspended in medium, which contained 30% FBS, 2 mmol/L glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, 1% deionized BSA, 10 mmol/L beta-mercaptoethanol, 1 mmol/L dexamethasone, 33 µg/ml holo-transferrin, 10 ng/ml SCF, 1 ng/ml IL-3 and 1 ng/ml GM-CSF (Sigma, St. Louis, MO), and 1 U/ml human recombinant EPO (Amgen Inc, Thousand Oaks, CA) Erythroid progenitor cells differentiated from hematopoietic CD34+ progenitor cells of fetal liver, cord blood, bone marrow and peripheral blood origin Biological replicates: 2 fetal liver, 3 cord blood, 3 bone marrow, 3 peripheral blood origin
2012-05-31 | E-GEOD-37869 | biostudies-arrayexpress
Project description:JAK/STAT pathway plays important roles in controlling Drosophila intestinal homeostasis and regulating the ISC proliferation and differentiation. However,the downstream targets of its transcription factor-STAT92E remain largely unknown.To further identify the regualtory mechanisms of the JAK/STAT pathway in controlling intestinal homeostasis,we performed the ChIP-Seq assay with mouse raised STAT92E antibody using JAK/STAT signaling highly activated adult intestines.Through the ChIP assay, we have identified over 1000 significant peaks (p<0.01) around the putative targets.The well-characterized JAK/STAT downstream targets including Domeless,Socs36E,STAT92E and chinmo were identified in our ChIP assay,indicating that our experiment is workable to identify novel JAK/STAT downstream targets in adult intestines.This work will provide insights into our understanding of regulatory mechanisms of JAK/STAT signaling during Drosophila intestinal development. Identify the ChIP peaks of STAT92E antibody using JAK/STAT signaling highly actived Drosophila adult intestines, compared with input libaray as the control
2015-05-12 | E-GEOD-67346 | biostudies-arrayexpress
Project description:To identify the mechanisms controlling chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) in humans, we analyzed genome-wide transcription dynamics in three myeloid leukemia cell lines (K562, HL-60, and THP1) using high-throughput sequencing technology. Using KEGG analysis, we found that the ERK/MAPK, JAK-STAT and ErbB pathways promoted proliferation and metabolism in CML. However, in AML, differentiation and apoptosis blocking resulted in the accumulation of blast cells in marrow. In addition, each cell type had unique characteristics. K562 cells are an ideal model for studying erythroid differentiation and globin gene expression. The chemokine signaling pathway and Fc gamma R-mediated phagocytosis were markedly upregulated in HL-60 cells. In THP1 cells, highly expressed genes ensured strong phagocytosis by monocytes. Further, we provide a new insight into myeloid development. The abundant data sets and well-defined analysis methods will provide a resource and strategy for further investigation of myeloid leukemia. Compare mRNA transcriptomes of three different cell lines
2013-10-09 | E-GEOD-46164 | biostudies-arrayexpress
Project description:Developing targeted therapy for cutaneous T cell lymphoma (CTCL) patients still requires actionable mutated genes and deregulated pathways to be identified. There is increasing evidence that activating mutations in JAK genes and deregulated JAK/STAT signaling are important mechanisms involved in multiple B and T cell malignancies, including CTCL. Therefore, in this study we focused on studying the mutational status of JAK1, JAK2 and JAK3 genes in a series of human CTCL lesions and cell lines using next-generation sequencing (NGS). We found that 7 of 48 (14.7%) of the analyzed cases harbored mutations in the JAK1 and JAK3 genes that mainly affected the pseudokinase domain of the corresponding proteins. On the basis of these results, we used a specific JAK inhibitor (INCB018424) in a series of CTCL cell lines with deregulated JAK/STAT activity. Treatment of CTCL cells with INCB018424 resulted in dose-dependent reduction of activated STAT expression, diminished cell viability, and increased apoptosis. We also studied global changes in gene expression in cells with mutated JAK1 and JAK3 proteins treated with INCB018424 and identified multiple genes that were differentially regulated by JAK/STAT signaling, such as FGF20 (upregulated) and EGR1 (downregulated). Thus, our results show that the detection of deregulated JAK/STAT signaling in CTCL lesions via JAK mutations or other surrogate markers may serve to indicate the clinical use of JAK/STAT inhibitors. 3 replicates of cells treated with DMSO or JAKi during 30 min and 3h
2015-10-31 | E-GEOD-68562 | biostudies-arrayexpress
Project description:JAK/STAT pathway plays important roles in controlling Drosophila intestinal homeostasis and regulating the ISC proliferation and differentiation. However,the downstream targets of its transcription factor-STAT92E remain largely unknown.To further identify the regualtory mechanisms of the JAK/STAT pathway in controlling intestinal homeostasis,we performed the ChIP-Seq assay with mouse raised STAT92E antibody using JAK/STAT signaling highly activated adult intestines.Through the ChIP assay, we have identified over 1000 significant peaks (p<0.01) around the putative targets.The well-characterized JAK/STAT downstream targets including Domeless,Socs36E,STAT92E and chinmo were identified in our ChIP assay,indicating that our experiment is workable to identify novel JAK/STAT downstream targets in adult intestines.This work will provide insights into our understanding of regulatory mechanisms of JAK/STAT signaling during Drosophila intestinal development.
2015-05-12 | GSE67346 | GEO
Project description:Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL.
2016-02-01 | GSE76061 | GEO
Project description:Naïve and activated T-cells has a different response to antigenic challenge. We examine whether a cytokine like IL-6 induces different responses through the Jak-STAT pathway to affect the functional characteristics of a given CD4 T‑cell subset. We isolated naïve and effector memory (Tem) CD4 T-cells to investigated STAT1 and STAT3 binding after 1-hour treatment with 20ng/ml IL-6 in the presence of anti-CD3/CD28.
2019-02-08 | E-MTAB-6273 | biostudies-arrayexpress
Project description:Combined gene expression and DNA occupancy profiling identifies JAK/STAT signaling as a valid therapeutic target of t(8;21) AML t(8;21) is commonly associated with acute myeloid leukemia (AML). The resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression and promoter occupancy profiling using a primary leukemia initiating cell-enriched population induced by AML1-ETO9a (AE9a). CD45, a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is greatly downregulated; furthermore JAK1 and JAK2 are upregulated in these leukemia cells. Consequently, JAK/STAT signaling is enhanced in the AE9a leukemia cells. Importantly, AE9a leukemia cells are highly susceptible to perturbation of JAK/STAT signaling, and a JAK2-selective inhibitor, TG101209, effectively targets these leukemia cells in vivo, suggesting the potential efficacy of JAK2 inhibitors in treating t(8;21) AML. Wild-type or AE9a leukemic samples in triplicate.
2012-09-04 | E-GEOD-15195 | biostudies-arrayexpress