Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

MN1 or MN1-TEL in the promonocytic cell line U937

ABSTRACT: Expression profiling of U937 derived cell lines with induced expression of MN1or MN1-TEL in combination with all-trans retinoic acid (ATRA) Keywords: expression profiling Two similar experiments (A and B, biological duplicates) were performed. Hybridization includes dye swaps. See experimental_design.jpg (below) for detailed setup of the study. In short, different time points after induction of MN1 or MN1-TEL were compared to uninduced samples. The effects of all-trans retinoic acid (ATRA) were also investigated

ORGANISM(S): Homo sapiens

SUBMITTER: Magda Meester

PROVIDER: E-GEOD-11441 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

MN1 affects expression of genes involved in hematopoiesis and can enhance as well as inhibit RAR/RXR-induced gene expression.

Meester-Smoor Magda A MA Janssen Marjolein J F W MJ Grosveld Gerard C GC de Klein Annelies A van IJcken Wilfred F J WF Douben Hannie H Zwarthoff Ellen C EC

Carcinogenesis 20080716 10

The oncoprotein meningioma 1 (MN1) is overexpressed in several subtypes of acute myeloid leukemia (AML) and overexpression was associated with a poor response to chemotherapy. MN1 is a cofactor of retinoic acid receptor/retinoic x receptor (RAR/RXR)-mediated transcription and this study identified genes in the promonocytic cell line U937 that were regulated by MN1. We found that MN1 can both stimulate and inhibit transcription. Combining MN1 expression with all-trans retinoic acid (ATRA), the li ...[more]

PMID: 18632758

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Project description:Myeloid differentiation is blocked in acute myeloid leukemia (AML), but the molecular mechanisms are not well characterized. MN1 is overexpressed in some AML patients and confers resistance to all-trans retinoic acid (ATRA)-induced differentiation. To understand the role of MN1 as a transcriptional regulator in myeloid differentiation, we fused transcriptional activation (VP16) or repression (M33) domains with MN1 and characterized these cells in vivo. Transcriptional activation of MN1 target genes induced myeloproliferative disease with long latency and differentiation potential to mature neutrophils. A large proportion of differentially expressed genes between leukemic MN1 and differentiation-permissive MN1VP16 cells belonged to the immune response pathway like Irf8 and Ccl9. As MN1 is a co-factor of MEIS1 and RARA, we compared chromatin occupancy between MN1, MEIS1 and RARA. Immune response genes that were upregulated in MN1VP16 cells were co-targeted by MN1 and MEIS1, but not RARA, suggesting that myeloid differentiation is blocked through transcriptional repression of shared target genes of MN1 and MEIS1. Constitutive expression of Irf8 or its target gene Ccl9 identified these genes as potent inhibitors of MN1-induced leukemia. Our data show that MN1 prevents activation of the immune response pathway, and suggest that restoration of Irf8 signalling as a novel therapeutic target in AML. C57BL/6J bone marrow cells were harvested from mice treated for 4 days with 150 mg 5-fluorouracil/kg and stimulated for 48 hours in DMEM supplemented with 15% FBS, 10 ng/mL hIL6, 6ng/mL mIL3, and 20ng/mL mSCF. The cells were infected with MN1 or MN1VP16 retroviral constructs by cocultivation with irradiated E86 viral producer cells in the presence of 5μg/mL protamine sulfate (Sigma) for 48 hours and then transplanted into lethally irradiated syngeneic recipient mice. 4 weeks after transplantation MN1, MN1VP16 GFP+ cells and Gr1+/CD11b+ bone marrow cells were FACS-sorted and analyzed by Affymetrix GeneChip Mouse 430 2.0 (43.000 probes) microarrays

Dataset Information

MN1 or MN1-TEL in the promonocytic cell line U937

Publications

MN1 affects expression of genes involved in hematopoiesis and can enhance as well as inhibit RAR/RXR-induced gene expression.

Similar Datasets

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