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Tumor suppressor role of Ezh2 in an NRASQ61K driven model of Early T-cell Precursor Acute Lymphoblastic Leukemia (RNA-Seq)

ABSTRACT: Purpose: To characterize transcriptional changes associated with homozygous inactivation the Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase Ezh2 in a mouse model of earlt T-cell precursor ALL (ETP-ALL) Methods: We sequenced mRNA from NRASQ61K transformed murine LSK-cells co-transduced with a self-inactivating Cre-vector. Cells were sorted for Cre-expression (lox-stop-loxRosa26-YFP) or expression of an inert control vector (GFP) and differentiated on OP9DL1 stroma with and without a functional Ezh2 gene. Results: Inactivation of Ezh2 in this model leads to accelerated leukemia development. Resulting gene expression changes are complex and include enrichment of genes associated with immature hematopoietic cells, Ras signaling and Cytokines and their cognate receptors. Conclusions: Inactivation of Ezh2 in our model leads to accentuated expression of early hematopoietic gene expression programs and to accentuated growth and survival signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE76602 | GEO | 2016/01/07

SECONDARY ACCESSION(S): PRJNA308129

REPOSITORIES: GEO

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Tumor suppressor role of Ezh2 in an NRASQ61K driven model of Early T-cell Precursor Acute Lymphoblastic Leukemia (RNA-Seq)

Project description:Purpose: To characterize transcriptional changes associated with homozygous inactivation the Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase Ezh2 in a mouse model of earlt T-cell precursor ALL (ETP-ALL) Methods: We sequenced mRNA from NRASQ61K transformed murine LSK-cells co-transduced with a self-inactivating Cre-vector. Cells were sorted for Cre-expression (lox-stop-loxRosa26-YFP) or expression of an inert control vector (GFP) and differentiated on OP9DL1 stroma with and without a functional Ezh2 gene. Results: Inactivation of Ezh2 in this model leads to accelerated leukemia development. Resulting gene expression changes are complex and include enrichment of genes associated with immature hematopoietic cells, Ras signaling and Cytokines and their cognate receptors. Conclusions: Inactivation of Ezh2 in our model leads to accentuated expression of early hematopoietic gene expression programs and to accentuated growth and survival signaling. Examination of mRNA levels between Ezh2ff and Ezh2ko in vivo, Ezh2ff and Ezh2ko in vitro.

2016-01-07 | E-GEOD-76602 | biostudies-arrayexpress

Tumor suppressor role of Ezh2 in an NRASQ61K driven model of Early T-cell Precursor Acute Lymphoblastic Leukemia (ChIP-Seq)

Project description:Purpose: To characterize changes in genome-wide H3K27me3 associated with homozygous inactivation the Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase Ezh2 in a mouse model of earlt T-cell precursor ALL (ETP-ALL) Methods: We performed Chip-seq for the H3K27me3 Chromatin mark on Ezh2ff and Ezh2ko cells NRASQ61K leukemias. Results: Inactivation of Ezh2 in this model leads to accelerated leukemia development. Resulting gene expression changes are complex and include enrichment of genes associated with immature hematopoietic cells, Ras signaling and Cytokines and their cognate receptors. Genes that lose K27me3 in Ezh2ko vs. Ezh2ff cells (ChIP-Seq) are enriched by GSEA in Ezh2ko vs Ezh2ff cells. Conclusions: Inactivation of Ezh2 in our model leads to accentuated expression of early hematopoietic gene expression programs, to accentuated growth and survival signaling and to transcriptonal enrichment of PRC2 targets. ChIP-Seq for H3K27me3 using Ezh2ff and Ezh2ko NRASQ61K leukemias harvested from leukemic mice and expanded on OP9DL1 cells.

2016-01-07 | E-GEOD-76601 | biostudies-arrayexpress

Tumor suppressor role of Ezh2 in an NRASQ61K driven model of Early T-cell Precursor Acute Lymphoblastic Leukemia (ChIP-Seq)

2016-01-07 | GSE76601 | GEO

The Histone Methyltransferases MLL1 and DOT1L Cooperate with Meningioma-1 to Induce AML [Mouse Mll1 ko RNA-seq]

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

The Histone Methyltransferases MLL1 and DOT1L Cooperate with Meningioma-1 to Induce AML [Mouse Dot1l ko RNA-seq]

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

The Histone Methyltransferases MLL1 and DOT1L Cooperate with Meningioma-1 to Induce AML [Mouse Dot1l ko RNA-seq]

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

The Histone Methyltransferases MLL1 and DOT1L Cooperate with Meningioma-1 to Induce AML [Mouse Mll1 ko RNA-seq]

2016-01-12 | E-GEOD-76749 | biostudies-arrayexpress

Expression data from RUNX1S291fs-mutant and/or Ezh2 conditional knockout Lineage-c-Kit+Sca-1+ (LSK) cells

Project description:Recent studies have showed that loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2, are often associated with RUNX1 mutations in myelodysplastic syndrome (MDS) patients. We established a novel MDS model mouse by transducing a RUNX1S291fs mutant in hematopoietic stem cells followed by deletion of Ezh2 and found that Ezh2 loss significantly promoted RUNX1S291fs-induced MDS. We retrovirally transduced RUNX1S291fs or empty-control into either Cre-ERT;Ezh2wt/wt or Cre-ERT;Ezh2flox/flox (CD45.2+) HSCs. The transduced cells were transplanted into lethally irradiated recipient mice together with life-saving CD45.1+ wild-type bone marrow cells. After deletion of Ezh2, gene expression analysis were performed on pooled bone marrow LSK cells isolated from WT, Ezh2Δ/Δ, RUNX1S291fs, and RUNX1S291fs/Ezh2Δ/Δ mice (n=2-4) and two distinct RUNX1S291fs/Ezh2Δ/Δ-MDS mouse.

2013-09-04 | E-GEOD-50537 | biostudies-arrayexpress

Expression profiling of secondary wild type (WT) and Ezh2-null murine MLL-AF9 AML

Project description:We evaluated gene expression changes in secondary recipient murine leukemia caused by retroviral overexpression of MLL-AF9. We compared wild-type (WT) leukemia cells with mutant leukemia cells after cre-mediated inactivation of a homozygous conditional allele for Ezh2, a component of the Polycomb Repressive Complex2. For WT cells, 4 biological replicates were hybridized. For Ezh2-null cells, 5 biological replicates were hybridized.

2012-02-22 | E-GEOD-34961 | biostudies-arrayexpress

Expression profiling of primary wild type (WT), Ezh2-null and Eed-null murine MLL-AF9 AML

Project description:We evaluated gene expression changes in murine leukemia caused by retroviral overexpression of MLL-AF9. We compared wild-type (WT) leukemia cells with mutant leukemia cells after cre-mediated inactivation of homozygous conditional alleles for Ezh2 or Eed, both of which are components of the Polycomb Repressive Complex2. For WT cells, 3 biological replicates were hybridized. For Ezh2-null cells, 4 biological replicates were hybridized. For Eed-cells, 3 biological replicates were hybridized.

2012-02-22 | E-GEOD-34959 | biostudies-arrayexpress

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