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Genome-wide analysis of mRNA expression alterations of sorted LysM-KI LSK cells versus control LSK cells

ABSTRACT: Microarrays were used to examine gene expression changes between bone marrow isolated haematopoeietic cell populations (LSK cells: Lin-Sca1+cKit+) populations of control and mutant (LysM-KI) mice. The LysM-KI mouse is a murine model which expresses an Idh1 (isocitrate dehydrogenase 1) mutation (Idh1-R132H) in cells of the myeloid lineage. Mutations in IDH1 (and IDH2) in humans are commonly found in cytogenetically normal acute myeloid leukemia as well as glioblastomas. The current study was initiated to understand how these mutations may affect leukemogenesis and myeloid cell development.

ORGANISM(S): Mus musculus

PROVIDER: GSE38589 | GEO | 2012/07/22

SECONDARY ACCESSION(S): PRJNA168199

REPOSITORIES: GEO

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Genome-wide analysis of mRNA expression alterations of sorted LysM-KI LSK cells versus control LSK cells

Project description:Microarrays were used to examine gene expression changes between bone marrow isolated haematopoeietic cell populations (LSK cells: Lin-Sca1+cKit+) populations of control and mutant (LysM-KI) mice. The LysM-KI mouse is a murine model which expresses an Idh1 (isocitrate dehydrogenase 1) mutation (Idh1-R132H) in cells of the myeloid lineage. Mutations in IDH1 (and IDH2) in humans are commonly found in cytogenetically normal acute myeloid leukemia as well as glioblastomas. The current study was initiated to understand how these mutations may affect leukemogenesis and myeloid cell development. Total RNA obtained from bone marrow sorted LSK cells of mutant LysM-KI and control individual mice.

2012-07-21 | E-GEOD-38589 | biostudies-arrayexpress

Idh1-R132H mutation increases murine hematopoietic progenitors and alters epigenetics.

Project description:Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequent in human glioblastomas1 and cytogenetically normal acute myeloid leukemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the M-bM-^@M-^\oncometaboliteM-bM-^@M-^] R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukemogenesis. Here we report the characterization of conditional knock-in mice in which the most common IDH1 mutation, Idh1-R132H, is inserted into the endogenous murine Idh1 locus and is expressed in cells of the hematopoietic (Vav-KI) or more specifically in cells of the myeloid (LysM-KI) lineage. These mutants show increased numbers of early hematopoietic progenitors and develop splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells exhibit both hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1/2-mutant AML. Thus, our study is the first to describe the generation of conditional Idh1-R132H-KI mice. Furthermore, our study is also the first report showing the induction of a leukemic DNA methylation signature in a modeled system and sheds light on the mechanistic links between IDH1 mutation and human AML. DNA methylation profiling in LSK cells from IDH1-R132H knock-in mice vs. control mice

2012-07-22 | E-GEOD-38687 | biostudies-arrayexpress

Idh1-R132H mutation increases murine hematopoietic progenitors and alters epigenetics.

Project description:Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequent in human glioblastomas1 and cytogenetically normal acute myeloid leukemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the “oncometabolite” R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukemogenesis. Here we report the characterization of conditional knock-in mice in which the most common IDH1 mutation, Idh1-R132H, is inserted into the endogenous murine Idh1 locus and is expressed in cells of the hematopoietic (Vav-KI) or more specifically in cells of the myeloid (LysM-KI) lineage. These mutants show increased numbers of early hematopoietic progenitors and develop splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells exhibit both hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1/2-mutant AML. Thus, our study is the first to describe the generation of conditional Idh1-R132H-KI mice. Furthermore, our study is also the first report showing the induction of a leukemic DNA methylation signature in a modeled system and sheds light on the mechanistic links between IDH1 mutation and human AML.

2012-07-22 | GSE38687 | GEO

DNA methylation in Vav-IDH1-KI mouse haematopoietic stem cells

Project description:Mutations in isocitrate dehydrogenase-1 (IDH1 R132) and -2 (IDH2 R140 and R172), which confer neomorphic enzymatic activity converting αKG (α-ketoglutarate) to D-2-hydroxyglutarate (D2HG), occur commonly in acute myeloid leukemia (AML). Mutant IDH1 alters epigenetics and increases haematopoietic progenitors in vivo, consistent with D2HG-mediated inhibition of TET2 5-methylcytosine hydroxylase. As TET2 mutations are mutually exclusive with IDH1/2 mutations and confer a similar phenotype, it has been widely believed that the oncogenicity of mutant IDH1/2 is due to TET2 inhibition. However, IDH1/2 mutations may have additional effects explaining the clinical features of MDS/MPN/AML. Here we show that mutant IDH1 downregulates ATM, thereby inhibiting DNA damage responses and increasing genomic instability. To investigate potential mechanisms of ATM downregulation, we examined ATM promoter DNA methylation in Vav-IDH1-KI long term haematopoietic stem cells (LT-HSC), short term haematopoietic stem cells (ST-HSC) and multipotent progenitors (MPP).

2017-08-23 | GSE66536 | GEO

DNA methylation alterations and transcriptional gene silencing induced by IDH1 R132H mutation [Illumina]

Project description:The cytosolic NADP+-dependent isocitrate dehydrogenase IDH1 is frequently mutated in human cancers. Recent studies have shown that IDH1 mutant primary glioblastomas (GBM) and acute myeloid leukemias (AML) display robust association with CpG island methylator phenotype (CIMP). Such observations bring into question whether IDH1 mutations directly contribute to the development of CIMP or if the hypermethylation phenotype precedes acquisition of IDH1 mutations. To reveal the effects of IDH1 mutations on DNA methylation and gene expression, we introduced the most frequently observed IDH1 mutation, R132H, into a human cancer cell line through gene targeting. We profiled changes in methylation at over 27,000 CpG dinucleotides spanning 14,475 unique gene regions and characterized genome-wide gene expression alterations resulting from IDH1R132H knockin. We observed consistent changes in both DNA methylation and gene expression when comparing two independent IDH1R132H knockin clones to their wild-type parent, and report hypermethylation of over 2,000 loci, the majority of which contained preexisting methylation in IDH1WT parental cells. These loci exhibit the same trend in primary TCGA glioblastoma tumors with mutant IDH1 as compared to those with wild-type IDH1 and have significant overlap with genes hypermethylated in glioma-CIMP+ tumors. Furthermore, we identify specific DNA methylation and gene expression alterations which correlate with IDH1 mutations in our cell-line model as well as primary glioblastomas, including hypermethylation and transcriptional silencing of RBP1. The presented data provide insight on epigenetic alterations induced by IDH1 mutations and support a contributory role for IDH1 mutants in regulation of DNA methylation and gene expression in human cancer cells. Comparison of IDH1 R132H and wild-type HCT116 cells as well as HOG cells overexpressing either wild-type IDH1 or IDH1 R132H

2012-08-13 | E-GEOD-31133 | biostudies-arrayexpress

Differential gene expression in IDH1-R132H Tumor Neurospheres generated from a mouse model of Low Grade Glioma

Project description:IDH1-R132H is expressed in Low Grade Glioma (LGG) in combination with mutation in ATRX and TP53 genes. IDH1-R132H results in gain of function with production of 2-hydroxygluatrate, that in turn generates a hypermethylatyed phenotype in DNA and histone with consequences in epigenetic regulation of gene expression. Here we will compare the gene expression profile between IDH1-R132H and IDH1 Wt tumor neurospheres.

2019-03-18 | GSE94974 | GEO

Differential gene expression in IDH1-R132H Low Grade Glioma animal brain tumors brain in response to 10 Gy of radiation

Project description:IDH1-R132H is expressed in Low Grade Glioma (LGG) in combination with loss of function mutation in ATRX and TP53 genes. IDH1-R132H results in gain of function with production of 2-hydroxygluatrate, that in turn generates a hypermethylatyed phenotype in DNA and histone with consequences in epigenetic regulation of gene expression. Here we will compare the gene expression profile between IDH1-R132H and IDH1 Wt LLG animal brain tumors in reponse to radiation

2019-03-18 | GSE94975 | GEO

Effect of IDH1 mutation induced by doxycycline on gene expression during VSVΔ51 infection in LN-229-TRE-R132H glioblastoma cells

Project description:To investigate whether IDH1 mutation influence the effects of oncolytic virus VSVΔ51, we transduced doxycycline-inducible IDH1-R132H lentiviruses into LN-229 to establish the LN-229-TRE-R132H cell line. We then performed gene expression profiling analysis using data obtained from RNA-seq of LN-229-TRE-R132H cells infected with or without VSVΔ51 in the presence or absence of IDH1 mutation induced by doxycycline.

2023-09-19 | GSE208634 | GEO

Differential gene expression in IDH1-R132H low grade glioma animal brain tumors brain in response to 20 Gy of radiation

Project description:IDH1-R132H is expressed in Low Grade Glioma (LGG) in combination with loss of function mutation in ATRX and TP53 genes. IDH1-R132H results in gain of function with production of 2-hydroxygluatrate, that in turn generates a hypermethylated phenotype in DNA and histone with consequences in epigenetic regulation of gene expression. Here we will compare the gene expression profile between IDH1-R132H and IDH1 Wt LLG moribund animal brain tumors and identify key genes responsible for the phenotype of this subtype of glioma.

2018-02-10 | GSE94902 | GEO

Project description:IDH1-R132H mutant

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