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Changes in gene expression resulting from expression of MN1 in human CD34+ cells

ABSTRACT: Reintroduction of CEBPA in MN1-overexpressing hematopoietic cells prevents their hyper-proliferation and restores myeloid differentiation. Forced expression of MN1 in primitive mouse hematopoietic cells causes acute myeloid leukemia and impairs all-trans retinoic acid (ATRA) induced granulocytic differentiation. Here, we studied the effects of MN1 on myeloid differentiation and proliferation using primary human CD34+ hematopoietic cells, lineage depleted mouse bone marrow cells, and bipotential (granulocytic/monocytic) human AML-cell lines. We show that exogenous MN1 stimulated the growth of CD34+ cells, which was accompanied by enhanced survival and increased cell cycle traverse in cultures supporting progenitor cell growth. Forced MN1 expression impaired both granulocytic and monocytic differentiation in vitro in primary hematopoietic cells and AML cell lines. Endogenous MN1 expression was higher in human CD34+ cells compared to both primary and in vitro differentiated monocytes and granulocytes. Microarray and real time RT-PCR analysis of MN1-overexpressing CD34+ cells showed down regulation of CEBPA and its downstream target genes. Re-introduction of conditional and constitutive CEBPA overcame the effects of MN1 on myeloid differentiation and inhibited MN1-induced proliferation in vitro. These results indicate that down regulation of CEBPA activity contributes to MN1-modulated proliferation and impaired myeloid differentiation of hematopoietic cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE16745 | GEO | 2010/10/26

SECONDARY ACCESSION(S): PRJNA117443

REPOSITORIES: GEO

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Changes in gene expression resulting from expression of MN1 in human CD34+ cells

Project description:Reintroduction of CEBPA in MN1-overexpressing hematopoietic cells prevents their hyper-proliferation and restores myeloid differentiation. Forced expression of MN1 in primitive mouse hematopoietic cells causes acute myeloid leukemia and impairs all-trans retinoic acid (ATRA) induced granulocytic differentiation. Here, we studied the effects of MN1 on myeloid differentiation and proliferation using primary human CD34+ hematopoietic cells, lineage depleted mouse bone marrow cells, and bipotential (granulocytic/monocytic) human AML-cell lines. We show that exogenous MN1 stimulated the growth of CD34+ cells, which was accompanied by enhanced survival and increased cell cycle traverse in cultures supporting progenitor cell growth. Forced MN1 expression impaired both granulocytic and monocytic differentiation in vitro in primary hematopoietic cells and AML cell lines. Endogenous MN1 expression was higher in human CD34+ cells compared to both primary and in vitro differentiated monocytes and granulocytes. Microarray and real time RT-PCR analysis of MN1-overexpressing CD34+ cells showed down regulation of CEBPA and its downstream target genes. Re-introduction of conditional and constitutive CEBPA overcame the effects of MN1 on myeloid differentiation and inhibited MN1-induced proliferation in vitro. These results indicate that down regulation of CEBPA activity contributes to MN1-modulated proliferation and impaired myeloid differentiation of hematopoietic cells Human BM derived CD34+ cells (Stemcell Technologies, Vancouver, BC, Canada) were expanded for 2 days and transduced with MSCV-IRES-GFP or MSCV-MN1-IRES-GFP retrovirus for another 2 days. One day later RNA was isolated from GFP+/CD34+ FACS-sorted cells using Trizol (Sigma) and samples were subjected to micro array analysis following Affymetrix protocols (Affymetrix, Santa Clara, CA) using the GeneChip Human U133 Plus 2.0 array

2010-10-26 | E-GEOD-16745 | biostudies-arrayexpress

Next Generation Sequencing Characterization of Hematopoietic Stem and Progenitors Cells in Human Systemic Lupus Eryhtematosus

Project description:Purpose: Next-generation sequencing (NGS) technology was exploited to map genome-wide expression profile of hematopoietic stem and progenitor cells (HSPCs) in Systemic Lupus Erythematosus (SLE). Results: Transcriptomic analysis of lupus HSPCs indicates activation, displayed increased proliferation and replicative stress, and profoundly prefer to differentiate towards myeloid/granulocytic lineage. Gene expression analysis suggests arrest of differentiation as key regulators including Cebpa, Cebpe, Irf8 are suppressed.

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Single-cell RNA-sequencing of differentiation myeloid cells

Project description:During granulocyte-macrophage colony-stmulating factor (GM-CSF) driven ex vivo myeloid differentiation of mouse hematopoietic stem/progenitor cells defined as Lineage negative cKit positive Sca-1 postive (LSK) cells, LSK cells after Cxxc5 knockdown makes more granulocytic cells than monocytic cells. To study this effect of Cxxc5 knockdown during myeloid cell differentiation, we performed a single-cell RNA sequencing of differentiating myeloid cells and analyzed the transcriptome of these cells.

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Enhancer and transcription factor dynamics within the granulocytic-monocytic lineage reveal an early differentiation block in Cebpa null progenitors

Project description:Myeloid cells of the granulocytic-monocytic (GM) lineage develop in a process orchestrated mainly by the transcription factors PU.1 and CEBPA, but how these factors collaborate on a global scale during GM-lineage differentiation remains uncharacterized. To address this question we have combined epigenetic profiling, transcription factor binding and gene expression analyses of successive stages of murine GM-lineage differentiation and show that PU.1 and CEBPA binds to GM enhancers with distinct kinetics. Surprisingly, we find no evidence of a pioneering function of PU.1 during GM-lineage differentiation but instead delineate a set of GM enhancers that appears to open in a CEBPA-dependent manner. Analyses of Cebpa null bone marrow demonstrate that CEBPA controls PU.1 levels and, unexpectedly, that the loss of CEBPA results in a very early differentiation block. These data are consistent with a model involving an extensive functional interplay between PU.1 and CEBPA in driving GM-lineage differentiation.

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LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML

Project description:Lsd1KO and ATRA treatment in Hoxa9/Meis1- and MN1-transformed myeloid progenitor cells LSD1 has emerged as a promising epigenetic target in the treatment of acute myeloid leukemia (AML). Inhibition of LSD1 has been shown to induce differentiation and facilitate the responsiveness of AML cells to all-trans retinoic acid. We used two murine AML models based on retroviral overexpression of Hoxa9/Meis1 (H9M) or MN1 to study the effect of Lsd1 knockout in AML. The conditional knockout of Lsd1 resulted in differentiation with both granulocytic and monocytic features in H9M-induced AML cells and enhanced their responsiveness towards ATRA treatment, which was not seen in MN1-driven AML. It also extended the survival of mice with H9M-driven AML. To identify molecular changes associated with the loss of Lsd1, we performed whole transcriptome analysis by RNA sequencing of H9M and MN1 Lsd1 fl/fl (Ctrl) and Lsd1cKO cells with or without ATRA treatment. The experiment was done in triplicates. The conditional knockout led to a broad increase in the expression of multiple genes regulated by the important myeloid transcription factors GFI1 and PU.1. These include the transcription factors GFI1B and IRF8, which may be relevant for the observed differentiation response.

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KSRP specifies monocytic and granulocytic differentiation through regulating miR-129 biogenesis and RUNX1 expression

Project description:We used CD34-positive cells isolated from cord blood to differentiate to granulocytic and monocytic lineages, respectively. Poly A-enriched RNA-seq was performed on the day 5, 10 and 15 samples of both granulocytic and monocytic lineages.

2017-08-01 | GSE87088 | GEO

Transcription profiling of human primary CD34+ cells undergoing granulocytic differentiation cultured under 5% and 20% O2 levels

Project description:Little is known about the global transcriptional program underlying granulocytic (G) commitment, differentiation and maturation. Using DNA microarrays and Q-RT-PCR, we examined the transcriptional profile of G differentiation of human CD34-positive hematopoietic stem and progenitor cells cultured with interleukin-3, interleukin-6 granulocyte colony stimulating factor and stem cell factor. The goal this study was to identify genes involved in the various facets of G differentiation including commitment, expansion, differentiation and functional capacity. This SuperSeries is composed of the following subset Series:; GSE5917: Temporal expression profile of granulocytic differentiation of primary CD34+ cells cultured under 20% O2 levels; GSE5918: Temporal expression profile of granulocytic differentiation of primary CD34+ cells cultured under 5% O2 levels; GSE6792: The transcriptional patterns of mature normal PB neutrophils (granulocytes) was examined and used as a control against which the transcriptional programs of cultured granulocytes and granulocytic cells lines can be compared. Experiment Overall Design: Refer to individual Series

2008-06-14 | E-GEOD-5922 | biostudies-arrayexpress

Identification of transcripts regulated by CEBPA in K562

Project description:To investigate the effect of CEBPA on the expression of mRNAs and long non-coding RNAs ( lncRNAs), we utilized the K562 AML cell line carrying a stable and Tet-on inducible CEBPA allele. K562 cells lack endogenous CEBPA and restoration of its expression induces proliferation arrest and granulocytic differentiation . Based on the expression of known CEBPA transcriptional targets, we selected RNA extracted from 48 hours of induction (CEBPA) together with RNA extracted from control-induced cells (CTR). 4 biological replicates for each sample have been utilized.

2014-09-01 | E-GEOD-58743 | biostudies-arrayexpress

Identification of transcripts regulated by CEBPA in K562

2014-09-01 | GSE58743 | GEO

Transcriptional repression of c-Myb and GATA-2 is involved in the effects of C/EBPα in p210 BCR/ABL-expressing cells

Project description:Levels of C/EBPα are low in myeloid blast crisis (BC) of chronic myelogenous leukemia (CML) and its expression in p210BCR/ABL-expressing hematopoietic cells induces granulocytic differentiation, inhibits proliferation and suppresses leukemogenesis. To assess the mechanisms involved in these effects, C/EBPα targets were identified by microarray analyses. Upon C/EBPα activation, expression of c-Myb and GATA-2 was repressed in 32D-BCR/ABL, K562 and CML-BC primary cells but only c-Myb levels decreased slightly in CD34+ normal progenitors. The role of these two genes for the biological effects of C/EBPα was assessed by perturbing their expression in K562 cells. Expression of c-Myb blocked the proliferation inhibition and differentiation-inducing effects of C/EBPα while c-Myb siRNA treatment enhanced C/EBPα-mediated proliferation inhibition and induced changes in gene expression indicative of monocytic differentiation. GATA-2 expression suppressed the proliferation inhibitory effect of C/EBPα but blocked in part the effect on differentiation; GATA-2 siRNA treatment had no effects on C/EBPα induction of differentiation but inhibited proliferation of K562 cells, alone or upon C/EBPα activation. In summary, the effects of C/EBPα in p210BCR/ABL -expressing cells depend, in part, on transcriptional repression of c-Myb and GATA-2. Since perturbation of c-Myb and GATA-2 expression has non identical consequences for proliferation and differentiation of K562 cells, the effects of C/EBPα appear to involve different transcription-regulated targets.

2008-06-13 | GSE11766 | GEO

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