Abstract
Mutations of isocitrate dehydrogenase 1 (IDH1) and IDH2 in acute myeloid leukemia (AML) cells produce the oncometabolite R-2-hydroxyglutarate (R-2HG) to induce epigenetic alteration and block hematopoietic differentiation. However, the effect of R-2HG released by IDH-mutated AML cells on the bone marrow microenvironment is unclear. Here, we report that R-2HG induces IκB kinase-independent activation of NF-κB in bone marrow stromal cells. R-2HG acts via a reactive oxygen species/extracellular signal-regulated kinase (ERK)-dependent pathway to phosphorylate NF-κB on the Thr254 residue. This phosphorylation enhances the interaction of NF-κB and the peptidyl-prolyl cis-trans isomerase PIN1 and increases the protein stability and transcriptional activity of NF-κB. As a consequence, R-2HG enhances NF-κB-dependent expression of cytokines including IL-6, IL-8 and complement 5a to stimulate proliferation of AML cells. In addition, R-2HG also upregulates vascular endothelial adhesion molecule 1 and CXCR4 in stromal cells to enhance the contact between AML and stromal cells and attenuates chemotherapy-induced apoptosis. More importantly, we validated the R-2HG-activated gene signature in the primary bone marrow stromal cells isolated from IDH-mutated AML patients. Collectively, our results suggest that AML cell-derived R-2HG may be helpful for the establishment of a supportive bone marrow stromal niche to promote AML progression via paracrine stimulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Complement C5a / genetics
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Complement C5a / metabolism
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Gene Expression Regulation, Leukemic*
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Glutarates / metabolism*
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Glutarates / pharmacology
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Interleukin-8 / genetics
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Interleukin-8 / metabolism
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Isocitrate Dehydrogenase / genetics
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Isocitrate Dehydrogenase / metabolism
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Junctional Adhesion Molecule B / genetics
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Junctional Adhesion Molecule B / metabolism
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism*
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Leukemia, Myeloid, Acute / pathology
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Mesenchymal Stem Cells / drug effects*
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Mesenchymal Stem Cells / metabolism
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Mesenchymal Stem Cells / pathology
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mutation
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Myeloid Cells / drug effects*
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Myeloid Cells / metabolism
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Myeloid Cells / pathology
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NF-kappa B / genetics*
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NF-kappa B / metabolism
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NIMA-Interacting Peptidylprolyl Isomerase / genetics
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NIMA-Interacting Peptidylprolyl Isomerase / metabolism
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Paracrine Communication / drug effects*
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Paracrine Communication / genetics
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Phosphorylation
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Primary Cell Culture
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Protein Stability
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Reactive Oxygen Species / metabolism
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / metabolism
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Signal Transduction
Substances
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CXCR4 protein, human
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Glutarates
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IL6 protein, human
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Interleukin-6
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Interleukin-8
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Junctional Adhesion Molecule B
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NF-kappa B
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NIMA-Interacting Peptidylprolyl Isomerase
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Reactive Oxygen Species
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Receptors, CXCR4
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alpha-hydroxyglutarate
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Complement C5a
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IDH2 protein, human
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Isocitrate Dehydrogenase
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IDH1 protein, human
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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PIN1 protein, human