Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genome wide analysis of SOCS2 dependent gene expression profile in bone marrow LSK following 5-Fluorouracil treatment

ABSTRACT: Hematopoietic stem cells (HSC) promptly adapt hematopoiesis to stress conditions, such as infection and cancer, by replenishing bone marrow (BM)-derived circulating populations while preserving the stem cell reservoir. SOCS2, a feedback inhibitor of JAK/STAT pathways is expressed in most primitive HSC and is upregulated in response to STAT5-inducing cytokines. We demonstrate that Socs2 deficiency unleashes HSC proliferation in vitro sustaining STAT5 phosphorylation in response to the hematopoietic cytokines IL-3, thrombopoietin (TPO) and GM-CSF. In vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-fluorouracil and, in turn, induces exhaustion of long-term HSC function along serial BM transplantations. These findings unveiled a new regulatory role for SOCS2 in normalizing HSC functions under hematopoietic stress and prompted its investigation for involvement in malignant hematopoiesis. Indeed, in acute myeloid and lymphoblastic leukemias high levels of SOCS2 characterize unfavorable subclasses with MLL and BCR/ABL abnormalities. Analysis of gene expression profiles showed that high SOCS2 positively correlates with a pool of genes that are significatively enriched of members of the stemness signature described in acute myeloid leukemia. Unexpectedly, in acute leukemias, SOCS2 and its related genes are not controlled by STAT5 signaling, they are rather part of regulatory networks fronted by IKZF1/Ikaros and MEF2C, two key hematopoietic stemness-related transcriptional factors that, independently, have been described in leukemias but never linked together in controlling SOCS2 expression and unfavorable leukemia outcome.

ORGANISM(S): Mus musculus

PROVIDER: GSE66065 | GEO | 2015/06/01

SECONDARY ACCESSION(S): PRJNA275803

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Label-free quantitative proteomics analysis of bone marrow cells of MK-LCM WT versus KO mice

Project description:High ploidy large cytoplasmic megakaryocytes (LCM) are critical negative regulators of hematopoietic stem cells (HSC) and are responsible for platelet formation. Using a mouse knockout model with normal megakaryocyte numbers but essentially devoid of LCM (MK-LCM KO), we demonstrated a pronounced increase in bone marrow HSC concurrent with endogenous mobilization and extramedullary hematopoiesis. When HSC isolated from a MK-LCM KO microenvironment were transplanted in lethally irradiated mice, the absence of LCM increased HSC in BM, blood and spleen. Severe thrombocytopenia was observed in animals with diminished LCM, although there was no change in megakaryocyte ploidy distribution. In contrast, WT HSC-generated LCM regulated a normal HSC pool and prevented thrombocytopenia. The present label-free quantitative LC-MSMS data was used to determine proteins that are differentially expressed in bone marrow cells of MK-LCM WT versus MK-LCM KO mice.

2023-05-10 | PXD040423 | Pride

Leukemic hematopoietic stem cell FLA2

Project description:Sca1+Lineage-cKit+ fetal liver (FL) and bone marrow (BM) cells were sorted and infected with Hoxa9+Meis retroviral particles, which provided fully leukemic complement to hematopoietic cells. These cells were injected into mice and leukemia onset was monitored in vivo. Leukemic stem cell (L-HSC) frequencies of these primary leukemias were evaluated using limiting dilution stem cell transfer in secondary recipients. The L-HSC frequency is near absolute for the FLA2 leukemia (around 1 L-HSC per 1.4 total leukemic bone marrow cells), whereas the other leukemias (FLB1, FLB2 and BM-derived leukemias) generated within the same experiment have a wide range of L-HSC frequencies. Keywords: other

2012-06-04 | GSE7235 | GEO

mRNA profiles of bone marrow and splenic hematopoietic stem cells after 5-FU challenge

Project description:Under stress hematopoiesis, previous studies have suggested the migration of hematopoietic stem cells (HSCs) from bone marrow (BM) to extramedullary sites such as spleen. However, there is little direct evidence of HSC migration from BM to spleen. Here, we induced myeloablation via 5-fluorouracil (5-FU) and showed the direct evidence of HSC migration from BM to spleen during hematopoietic regeneration via a photoconvertible fluorophore. We found that during hematopoietic regeneration, there were mechanistic differences for HSC migration during early (day 3 to 8) and late phase (day 11 to 14). During steady-state, HSCs preferentially migrated to BM rather than spleen, but during the early phase HSC migration to spleen predominated. Indeed, in the early phase, HSC mobilization from BM was induced in G-CSF-dependent manners, while HSCs in the late phase gained significantly enhanced cell-autonomous motility, which was independent of chemotaxis. Collectively, HSC migration was dynamically changed during hematopoietic regeneration.

2023-12-01 | GSE248234 | GEO

CCCTC-binding factor is essential for the mouse hematopoietic stem cell maintenance and quiescence

Project description:Hematopoiesis is a series of lineage differentiation programs initiated from hematopoietic stem cells (HSCs) in the bone marrow (BM). To maintain lifelong hematopoiesis, the pool of HSCs is precisely maintained by diverse molecular mechanisms. CCCTC-binding factor (CTCF) is a DNA-binding zinc-finger protein which regulates its target gene expression by organizing higher order chromatin structures. Currently, the role for CTCF in controlling HSC homeostasis is unknown. By using a tamoxifen-induced CTCF conditional knockout mouse system, we demonstrate that CTCF is a critical regulator for the homeostatic maintenance of adult HSCs by retaining HSC cell cycle quiescence. Acute systemic CTCF ablation leads to a severe BM failure and rapid shrinkage of multiple c-Kithi progenitor populations, including Sca-1+ HSCs in adult mice. Similarly, a hematopoietic system-confined CTCF depletion elicits an acute loss of HSCs and highly increased mortality. Mixed BM chimeras reconstituted together with the supporting BM reveal that CTCF deficiency-mediated HSC depletion is a cell-autonomous effect. Although c-Kithi myeloid progenitors were severely reduced after ablating Ctcf gene, c-Kitint common lymphoid progenitors and their progenies were less affected by the lack of CTCF. Whole transcriptome analyses show that CTCF deficiency results in an enhanced expression of the cell cycle-promoting program and CTCF-depleted HSCs express higher level of reactive oxygen species (ROS). Importantly, in vivo treatment with the antioxidant partially rescued the c-Kithi population and their quiescence. We conclude that CTCF is a pivotal player in maintaining adult HSC pool likely through regulating ROS-dependent HSC quiescence. We used gene expression microarray to elucidate CTCF-regulated gene profiles of the Lin−Sca-1+c-Kithi (LSKs) stem/progenitor populations.

2017-10-31 | GSE88995 | GEO

Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition

Project description:Adult hematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells and must respond to extracellular cues including cytokines. The JAK/STAT pathway is a highly conserved pathway, activated by many cytokines, in which tyrosine-phosphorylated STATs (pSTATs) function as transcription factors. STAT5 is a pivotal downstream mediator of several cytokines known to regulate hematopoiesis but its function in the HSC compartment remains poorly understood. Here we show that STAT5-deficient HSCs exhibited an unusual phenotype - reduced multi-lineage repopulation and self-renewal combined with reduced cell cycle entry and increased differentiation. This reflected not only loss of a canonical pSTAT5 transcriptional program but also loss of distinct functions mediated by tyrosine-unphosphorylated STAT5 (uSTAT5). Consistent with this concept expression of an unphosphorylatable STAT5B mutant constrained HSC differentiation, promoted HSC maintenance and upregulated transcriptional programs associated with quiescence and stemness. Moreover, treatment with a JAK1/2 inhibitor (ruxolitinib) increased the uSTAT5:pSTAT5 ratio, constrained HSC differentiation and proliferation and promoted HSC maintenance, thus phenocopying uSTAT5B overexpression. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function. In addition the demonstration that JAK inhibition promotes HSC maintenance has implications for gene therapy using HSCs and may contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.

2024-01-31 | GSE223680 | GEO

Gene expression data from sorted primary human cord blood samples

Project description:Experiments using xenografts show that some solid tumours and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSC). Despite promise, the relevance of the CSC model to human disease remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model based on sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSC) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSC and HSC, revealing the molecular machinery underlying stemness properties. Both stem cell programs were highly significant independent predictors of patient survival and also found in existing prognostic signatures. Thus, determinants of stemness influence clinical outcome of AML establishing that LSC are clinically relevant and not mere artifacts of xenotransplantation. Analysis of gene expression in FACS sorted cord blood fractions that were functionally determined to be enriched for HSC or not (6 and 6 respectively). 12 samples were hybridized to Affymetrix HG_U133A microarray [HG_U133A] or Affymetrix HG_U133B microarray [HC_U133B]

2011-08-27 | E-GEOD-30376 | biostudies-arrayexpress

Gene expression data from sorted and unsorted primary human acute myeloid leukemia (AML) samples

Project description:Experiments using xenografts show that some solid tumours and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSC). Despite promise, the relevance of the CSC model to human disease remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model based on sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSC) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSC and HSC, revealing the molecular machinery underlying stemness properties. Both stem cell programs were highly significant independent predictors of patient survival and also found in existing prognostic signatures. Thus, determinants of stemness influence clinical outcome of AML establishing that LSC are clinically relevant and not mere artifacts of xenotransplantation. Analysis of gene expression in FACS sorted AML fractions that were functionally determined to be enriched for LSC or not (25 and 29 respectively).

2011-08-27 | E-GEOD-30375 | biostudies-arrayexpress

Epigenetic extinction of fetal programming promotes leukemia stem cell activity

Project description:Acute leukemias are aggressive malignancies of developmentally arrested hematopoietic progenitors. We sought here to explore the possibility that changes in hematopoietic stem/progenitor cells during aging might alter the biology of leukemias arising from this tissue compartment. Using a mouse model of acute T-cell leukemia, we found that leukemias generated from fetal liver (FL) and adult bone marrow (BM) differed dramatically in their leukemia stem cell activity with FL leukemias showing markedly reduced serial transplantability as compared to BM leukemias. We present evidence that this difference is due to NOTCH1-driven autocrine IGF1 signaling which is active in FL cells, but restrained in BM cells by EZH2-dependent H3K27 trimethylation. Further, we confirmed this mechanism is operative in human disease, and show that enforced IGF1 signaling effectively limits leukemia stem cell activity. These findings demonstrate that resurrecting dormant fetal programs in adult cells may represent an alternate therapeutic approach in human cancer.

2018-09-27 | GSE118308 | GEO

Expression analysis of wild type and CCP3 deficient LT-HSCs

Project description:All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhances Hoxa1 expression leading to HSC self-renewal. Bap1E651A mice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.

2019-10-03 | GSE138298 | GEO

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [ATAC-Seq]

Project description:Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation, however cohesin-mutant leukemias do not show genomic instability. We hypothesized reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Bi-allelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation, and revealed an absolute requirement for cohesin in hematopoietic stem cell function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose-dependency for cohesin in regulating chromatin structure and hematopoietic stem cell function. ATAC-seq in murine c-kit+ cells for the following genotypes: Smc3 fl/+, Smc3 del/+, Flt3-ITD, Smc3 fl/del Flt3-ITD

2015-09-21 | E-GEOD-73215 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data