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DNA methylation changes induced by hypomethylating agent, Azacitidine (AZA); IDH1 inhibitor, BAY1436032 (BAY) and sequential and simultaneous combination of BAY and AZA in in vitro treated human (CD45+) cells isolated from the bone marrow of IDH1mut

ABSTRACT: Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis. Data for IDH1 inhibitors show that 30-40% of AML patients respond to monotherapy with a median duration of response of 8 months, suggesting that IDH1 inhibitors should be combined with other agents to improve efficacy. BAY 1436032 (BAY) is an oral pan-mutant IDH1 inhibitor currently undergoing phase 1 clinical trials. 5-Azacitidine (AZA) is a hypomethylating agent and can activate key epigenetically silenced pathways in AML cells, leading to an arrest of AML cell proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146502 | GEO | 2020/05/25

REPOSITORIES: GEO

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Gene expression changes induced by hypomethylating agent, Azacitidine (AZA) ; IDH1 inhibitor, BAY1436032 (BAY) and combination of BAY and AZA in sorted human (CD45+) cells from bone marrow of IDH1mut Patient derived Xenotransplantation mice model.

Project description:Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis. Data for IDH1 inhibitors show that 30-40% of AML patients respond to monotherapy with a median duration of response of 8 months, suggesting that IDH1 inhibitors should be combined with other agents to improve efficacy. BAY 1436032 (BAY) is an oral pan-mutant IDH1 inhibitor currently undergoing phase 1 clinical trials. 5-Azacitidine (AZA) is a hypomethylating agent and can activate key epigenetically silenced pathways in AML cells, leading to an arrest of AML cell proliferation.

2019-12-31 | GSE122428 | GEO

Gene expression changes induced by hypomethylating agent, Azacitidine (AZA); IDH1 inhibitor, BAY1436032 (BAY) and sequential and simultaneous combination of BAY and AZA in in vitro treated human (CD45+) cells isolated from the bone marrow of IDH1mut

2020-05-25 | GSE146503 | GEO

Gene expression changes induced by BAY1436032 (IDH1mut inhibitor) in sorted human (CD45+) cells from bone marrow of IDH1mut patient derived xenotransplantation mice model

2017-05-22 | GSE83485 | GEO

DNA methylation and gene expression changes induced by hypomethylating agent, Azacitidine (AZA), BAY1436032 (BAY) and sequential and simultaneous combination of BAY and AZA in in vitro treated human (CD45+) cells isolated from the bone marrow of IDH1mut

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-05-25 | GSE146504 | GEO

Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation

Project description:Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells rapidly induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem cell marker expression, suggesting a shared pro-leukemogenic effect. DNA methylation and gene expression profiling in IDH1/2 mutant vs. IDH1/2 wild-type AML

2010-12-03 | E-GEOD-24505 | biostudies-arrayexpress

Gene expression changes induced by overexpression of IDH1mut in the sorted mouse bone marrow cells

2013-11-05 | GSE45019 | GEO

Gene expression changes induced by overexpression of IDH1mut and treatment with 2HG in the sorted mouse bone marrow cells

2016-06-01 | GSE77594 | GEO

DNA methylation changes induced by overexpression of IDH1mut or treatment with 2HG in the sorted mouse bone marrow cells

2016-06-01 | GSE77828 | GEO

Gene expression changes induced by overexpression of IDH1mut and treatment with 2HG in the sorted mouse bone marrow cells

Project description:Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis. HoxA9 immortalised bone marrow cells from C57BJ/6 mice were tranduced with either empty vector or pSF91-IDH1wt-IRES-EGFP, or pSF91-IDH1mut-IRES-GFP and transplanted in irradiated recipient mice. Alternatively, HoxA9 immortalised cells transduced with empty vector transplanted mice were treated with R-2HG at dose of 1mg/day for four weeks. Four weeks after transplantation/treatment GFP+ cells were sorted from mouse bone marrow, from which total RNA ws extracted and subjected to microarray analysis.

2016-06-01 | E-GEOD-77594 | biostudies-arrayexpress

DNA methylation changes induced by overexpression of IDH1mut or treatment with 2HG in the sorted mouse bone marrow cells

Project description:Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis. HoxA9 immortalised bone marrow cells from C57BJ/6 mice were tranduced with either empty vector or pSF91-IDH1wt-IRES-EGFP, or pSF91-IDH1mut-IRES-GFP and transplanted in irradiated recipient mice. Alternatively, HoxA9 immortalised cells transduced with empty vector transplanted mice were treated with R-2HG at dose of 1mg/day for four weeks. Four weeks after transplantation/treatment GFP+ cells were sorted from mouse bone marrow, from which total DNA was extracted and subjected to Reduced Representation Bisulfite Sequencing (RRBS) to determine the genome-wide methylation signature.

2016-06-01 | E-GEOD-77828 | biostudies-arrayexpress

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