The Histone Methyltransferases MLL1 and DOT1L Cooperate with Meningioma-1 to Induce AML [Mouse ChIP-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76746 | GEO | 2016/01/12
SECONDARY ACCESSION(S): PRJNA308492
REPOSITORIES: GEO
Similar Datasets
Project description:Purpose: To characterize the genome-wide distribution of H3K79me2 in murine MN1 driven myeloid leukemia Methods: We performed Chip-seq for the H3K79me2 in leukemias isolated from moribund mice that had been injected with common myeloid progenitors (CMPs) transduced with MSCV-MN1-GFP Results: H3K79me2 is enriched at key loci that 1. are bound by MN1 in the data set of Heuser et al, (Cancer Cell. 2011 Jul 12;20(1):39-52.), 2. upregulated upon transduction with MN1, and lose expression upon deletion of the H3K79 methyltransferase Dot1l. Conclusions: A leukemogenic program in MN1 leukemias is marked by H3K79me2 and dependent on this mark ChIP-Seq for H3K79me2 using MN1 driven leukemias isolated from the bone marrow of moribund mice.
2016-01-12 | E-GEOD-76746 | biostudies-arrayexpress
Project description:Purpose: To characterize transcriptional changes associated with homozygous inactivation of Dot1l or Mll1 in MN1 driven AML Methods: We sequenced mRNA from murine LSK-cells transformed using forced expression of MN1 (MSCV-MN1-IRES-GFP), and transduced with Cre-vector to inactivate either Dot1l or Mll1. Cells were sorted for Cre-expression (pTomato fluorescent marker) or expression of an inert control vector. Results: Inactivation of either Dot1l or Mll1 in this model leads to a substantial delay or complete abrogation of leukemia development.Loss of Dot1l or Mll1 are associated with gene expression changes that have substantial overlap. In addition, genes that are downregulated follwing inactivation of Dot1l or Mll1 have substantial overlap with the gene set upregulated in MN1 transduced CMPs. Conclusions: MN1 mediated leukemogenesis is associated with a gene expression program that dependes on Mll1 and Dot1l
2016-01-12 | GSE76749 | GEO
Project description:Purpose: To characterize transcriptional changes associated with homozygous inactivation of Dot1l or Mll1 in MN1 driven AML Methods: We sequenced mRNA from murine LSK-cells transformed using forced expression of MN1 (MSCV-MN1-IRES-GFP), and transduced with Cre-vector to inactivate either Dot1l or Mll1. Cells were sorted for Cre-expression (pTomato fluorescent marker) or expression of an inert control vector. Results: Inactivation of either Dot1l or Mll1 in this model leads to a substantial delay or complete abrogation of leukemia development.Loss of Dot1l or Mll1 are associated with gene expression changes that have substantial overlap. In addition, genes that are downregulated follwing inactivation of Dot1l or Mll1 have substantial overlap with the gene set upregulated in MN1 transduced CMPs. Conclusions: MN1 mediated leukemogenesis is associated with a gene expression program that dependes on Mll1 and Dot1l Examination of mRNA levels between Dot1l f/f and Dot1l ko, and Mll1 f/f and Mll1 ko.
2016-01-12 | E-GEOD-76749 | biostudies-arrayexpress
Project description:Purpose: To characterize transcriptional changes associated with homozygous inactivation of Dot1l or Mll1 in MN1 driven AML Methods: We sequenced mRNA from murine LSK-cells transformed using forced expression of MN1 (MSCV-MN1-IRES-GFP), and transduced with Cre-vector to inactivate either Dot1l or Mll1. Cells were sorted for Cre-expression (pTomato fluorescent marker) or expression of an inert control vector. Results: Inactivation of either Dot1l or Mll1 in this model leads to a substantial delay or complete abrogation of leukemia development. Loss of Dot1l or Mll1 are associated with gene expression changes that have substantial overlap. In addition, genes that are downregulated follwing inactivation of Dot1l or Mll1 have substantial overlap with the gene set upregulated in MN1 transduced CMPs. Conclusions: MN1 mediated leukemogenesis is associated with a gene expression program that dependes on Mll1 and Dot1l
2016-01-12 | GSE76748 | GEO
Project description:Purpose: To characterize transcriptional changes associated with homozygous inactivation of Dot1l or Mll1 in MN1 driven AML Methods: We sequenced mRNA from murine LSK-cells transformed using forced expression of MN1 (MSCV-MN1-IRES-GFP), and transduced with Cre-vector to inactivate either Dot1l or Mll1. Cells were sorted for Cre-expression (pTomato fluorescent marker) or expression of an inert control vector. Results: Inactivation of either Dot1l or Mll1 in this model leads to a substantial delay or complete abrogation of leukemia development. Loss of Dot1l or Mll1 are associated with gene expression changes that have substantial overlap. In addition, genes that are downregulated follwing inactivation of Dot1l or Mll1 have substantial overlap with the gene set upregulated in MN1 transduced CMPs. Conclusions: MN1 mediated leukemogenesis is associated with a gene expression program that dependes on Mll1 and Dot1l Examination of mRNA levels between Dot1l f/f and Dot1l ko, and Mll1 f/f and Mll1 ko.
2016-01-12 | E-GEOD-76748 | biostudies-arrayexpress
Project description:The molecular mechanism defining susceptibility of normal cells to oncogenic transformation may be a valuable therapeutic target. We characterized the cell of origin and its critical pathways in MN1 leukemias. Common myeloid (CMP), but not granulocyte-macrophage progenitors (CMP) could be transformed by constitutively overexpressed MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that leukemogenicity of MN1 required the MEIS1/abdB-like HOX protein complex. Colocalization studies by ChIP-seq identified common chromatin targets of MN1 and MEIS1 that were associated with open chromatin and transcriptional activation. Transcriptional repression of MEIS1 target sites in established MN1 leukemias had antileukemic activity. As MN1 relies on but can not activate expression of MEIS1/abdB-like HOX proteins, transcriptional activity of these genes determines which cell is the cell of origin in MN1 leukemia. We have showed at the single cell level that CMPs, but not GMPs, are susceptible to MN1-induced transformation. To identify transcriptional differences between CMPs and GMPs that may explain this difference in susceptibilities to MN1 transformation we produced gene expression profiles (two biological replicates in each experimental arm) of bone marrow cells from MN1 leukemic mice and mature myeloid bone marrow cells (Gr1+/CD11b+) from healthy mice and compared those to already published gene expression profiles of CMPs and GMPs (Krivtsov, A.V., et al. (2006). Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818-822).
2011-05-19 | E-GEOD-22923 | biostudies-arrayexpress
Project description:Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic molecular marker in adult AML with normal cytogenetics, however its role in pediatric leukemia is unknown. We found elevated MN1 expression in 53 of 88 pediatric leukemia cases: significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia but no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL). Interestingly 17 of 19 cases harboring MLL-X fusions showed also elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM13). In a mouse MLL/ENL-induced leukemia MN1 overexpression resulted from retroviral provirus insertion. Strikingly co-expression of MN1 with MLL/ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. MN1 overexpression in MLL/ENL-carrying cells resulted in expansion of the L-GMP population and facilitated disease induction in secondary recipients. Gene expression profiling allowed to define a number of potential MN1 hematopoietic targets. Up-regulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse leukemias, as well as in some cases of pediatric leukemias overexpressing MN1. Taken together, our work suggests that MN1 overexpression is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-X fusion genes most probably through modification of a distinct gene expression program that leads to expansion of a leukemia initiating cell population. In three independent experiments bone marrow cells were transduced with MSCV-MN1-IRES/YFP or empty vector. 72h after transduction EYFP-positive cells were FACS-sorted and RNA isolated by ion-exchange chromatography with RNAmini (Qiagen) according to the manufacturerâs protocol
2010-04-08 | E-GEOD-13189 | biostudies-arrayexpress
Project description:Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic molecular marker in adult AML with normal cytogenetics, however its role in pediatric leukemia is unknown. We found elevated MN1 expression in 53 of 88 pediatric leukemia cases: significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia but no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL). Interestingly 17 of 19 cases harboring MLL-X fusions showed also elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM13). In a mouse MLL/ENL-induced leukemia MN1 overexpression resulted from retroviral provirus insertion. Strikingly co-expression of MN1 with MLL/ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. MN1 overexpression in MLL/ENL-carrying cells resulted in expansion of the L-GMP population and facilitated disease induction in secondary recipients. Gene expression profiling allowed to define a number of potential MN1 hematopoietic targets. Up-regulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse leukemias, as well as in some cases of pediatric leukemias overexpressing MN1. Taken together, our work suggests that MN1 overexpression is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-X fusion genes most probably through modification of a distinct gene expression program that leads to expansion of a leukemia initiating cell population.
2009-06-01 | GSE13189 | GEO
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
Project description:Purpose: To characterize the genome-wide distribution of H3K79me2 in human leukemia cell lines treated with the Dot1l inhibitor EPZ004777 or control Methods: We performed Chip-seq for the H3K79me2 on the leukemia cell lines Mutz3, Loucy and Molm14 after 6 days in culture in the presence of 3uM EPZ004777 or DMSO control Results: H3K79me2 is completely erased from key target genes such as the HOXA cluster. Conclusions: Exposure of Mutz3, Loucy and Molm14 to 3uM EPZ004777 erases H3K79 methylation globally as well as on key loci ChIP-Seq for H3K79me2 on human leukemia cell lines exposed for 6 days to the Dot1l inhibitor EPZ004777
2016-01-12 | E-GEOD-76745 | biostudies-arrayexpress