Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Replication study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate

ABSTRACT: The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from “The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate” by Ward and colleagues, published in Cancer Cell in 2010 (Ward et al., 2010). The experiments that will be replicated are those reported in Figures 2, 3 and 5. Ward and colleagues demonstrate the mutations in isocitrate dehydrogenase 2 (IDH2), commonly found in acute myeloid leukemia (AML), abrogate the enzyme’s wild-type activity and confer to the mutant neomorphic activity that produces the oncometabolite 2-hydroxyglutarate (2-HG) (Figures 2 and 3). They then show that elevated levels of 2-HG are correlated with mutations in IDH1 and IDH2in AML patient samples (Figure 5). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published by eLife.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cells

DISEASE(S): Cancer

SUBMITTER: Oliver Fiehn

PROVIDER: ST000548 | MetabolomicsWorkbench | Fri Jan 06 00:00:00 GMT 2017

REPOSITORIES: MetabolomicsWorkbench

ACCESS DATA

Json Xml

Similar Datasets

Novel IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia (expression)

Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in AML patients’ cells. Our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. To obtain insight into the molecular mechanism for the induction of granulocytic differentiation and cell death following inhibition of IDH1 mutant protein in primary AML cells, we performed gene expression microarrays following treatment with either GSK321 IDH1 inhibitor or Controls (DMSO or GSK990 inactive inhibitor). Primary IDH1 mutant acute myeloid leukemia (AML) mononuclear (MNC) cells were treated in suspension cultures in differentiating media for 6 days with 3 microM GSK990 or GSK321 and an equal volume of DMSO. Followed by microarray analysis after RNA extraction.

2015-09-21 | E-GEOD-72152 | biostudies-arrayexpress

Novel IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia (ERRBS)

Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in AML patients’ cells. Our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. To obtain insight into the molecular mechanism of the novel IDH1 mutant allosteric inhibitor, primary AML cells were treated with either GSK321 IDH1 active inhibitor or Controls (DMSO or GSK990 inactive inhibitor) followed by DNA extraction for ERRBS analysis. Primary IDH1 mutant acute myeloid leukemia (AML) mononuclear (MNC) cells were treated in suspension cultures in differentiating media for 6 days with 3 microM GSK990 or GSK321 and an equal volume of DMSO, Followed ERRBS analysis after DNA extraction.

2015-09-21 | E-GEOD-72247 | biostudies-arrayexpress

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

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

2020-05-25 | GSE146502 | 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

Novel IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia (ERRBS)

Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in AML patients’ cells. Our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. To obtain insight into the molecular mechanism of the novel IDH1 mutant allosteric inhibitor, primary AML cells were treated with either GSK321 IDH1 active inhibitor or Controls (DMSO or GSK990 inactive inhibitor) followed by DNA extraction for ERRBS analysis.

2015-09-21 | GSE72247 | GEO

Novel IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia (expression)

2015-09-21 | GSE72152 | GEO

Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes

Project description:Acute myeloid leukaemia (AML) is genetically a genetically heterogeneous condition. It was observed that mutations in the micro RNA mir142 co-occurred with mutations in isocitrate dehdrogenase genes IDH1 and 2. These experiments intend to investigate the interaction between miR142 and IDH in AML.

2020-06-05 | E-MTAB-8042 | biostudies-arrayexpress

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data