fumarates and Leukemia--Myeloid--Acute

fumarates has been researched along with Leukemia--Myeloid--Acute* in 2 studies

Other Studies

2 other study(ies) available for fumarates and Leukemia--Myeloid--Acute

Article	Year
Loss of miR-31-5p drives hematopoietic stem cell malignant transformation and restoration eliminates leukemia stem cells in mice. Science translational medicine, 2022, 01-26, Volume: 14, Issue:629 Topics: Animals; Fumarates; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; MicroRNAs; Neoplastic Stem Cells	2022
Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes. The Journal of biological chemistry, 2016, Feb-19, Volume: 291, Issue:8 The TET enzymes are members of the 2-oxoglutarate-dependent dioxygenase family and comprise three isoenzymes in humans: TETs 1-3. These TETs convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA, and high 5-hmC levels are associated with active transcription. The importance of the balance in these modified cytosines is emphasized by the fact that TET2 is mutated in several human cancers, including myeloid malignancies such as acute myeloid leukemia (AML). We characterize here the kinetic and inhibitory properties of Tets and show that the Km value of Tets 1 and 2 for O2 is 30 μm, indicating that they retain high activity even under hypoxic conditions. The AML-associated mutations in the Fe(2+) and 2-oxoglutarate-binding residues increased the Km values for these factors 30-80-fold and reduced the Vmax values. Fumarate and succinate, which can accumulate to millimolar levels in succinate dehydrogenase and fumarate hydratase-mutant tumors, were identified as potent Tet inhibitors in vitro, with IC50 values ∼400-500 μm. Fumarate and succinate also down-regulated global 5-hmC levels in neuroblastoma cells and the expression levels of some hypoxia-inducible factor (HIF) target genes via TET inhibition, despite simultaneous HIFα stabilization. The combination of fumarate or succinate treatment with TET1 or TET3 silencing caused differential effects on the expression of specific HIF target genes. Altogether these data show that hypoxia-inducible genes are regulated in a multilayered manner that includes epigenetic regulation via TETs and 5-hmC levels in addition to HIF stabilization. Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Dioxygenases; DNA-Binding Proteins; Fumarates; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Mice; Mixed Function Oxygenases; Mutation; Neuroblastoma; Proto-Oncogene Proteins; Succinic Acid	2016

Article

Year

Loss of miR-31-5p drives hematopoietic stem cell malignant transformation and restoration eliminates leukemia stem cells in mice.

Science translational medicine, 2022, 01-26, Volume: 14, Issue:629

Topics: Animals; Fumarates; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; MicroRNAs; Neoplastic Stem Cells

2022

Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes.

The Journal of biological chemistry, 2016, Feb-19, Volume: 291, Issue:8

The TET enzymes are members of the 2-oxoglutarate-dependent dioxygenase family and comprise three isoenzymes in humans: TETs 1-3. These TETs convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA, and high 5-hmC levels are associated with active transcription. The importance of the balance in these modified cytosines is emphasized by the fact that TET2 is mutated in several human cancers, including myeloid malignancies such as acute myeloid leukemia (AML). We characterize here the kinetic and inhibitory properties of Tets and show that the Km value of Tets 1 and 2 for O2 is 30 μm, indicating that they retain high activity even under hypoxic conditions. The AML-associated mutations in the Fe(2+) and 2-oxoglutarate-binding residues increased the Km values for these factors 30-80-fold and reduced the Vmax values. Fumarate and succinate, which can accumulate to millimolar levels in succinate dehydrogenase and fumarate hydratase-mutant tumors, were identified as potent Tet inhibitors in vitro, with IC50 values ∼400-500 μm. Fumarate and succinate also down-regulated global 5-hmC levels in neuroblastoma cells and the expression levels of some hypoxia-inducible factor (HIF) target genes via TET inhibition, despite simultaneous HIFα stabilization. The combination of fumarate or succinate treatment with TET1 or TET3 silencing caused differential effects on the expression of specific HIF target genes. Altogether these data show that hypoxia-inducible genes are regulated in a multilayered manner that includes epigenetic regulation via TETs and 5-hmC levels in addition to HIF stabilization.

Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Dioxygenases; DNA-Binding Proteins; Fumarates; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Mice; Mixed Function Oxygenases; Mutation; Neuroblastoma; Proto-Oncogene Proteins; Succinic Acid

2016