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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

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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

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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

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

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