RRC ID 68567
著者 Chen JY, Lai YS, Tsai HJ, Kuo CC, Yen BL, Yeh SP, Sun HS, Hung WC.
タイトル The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells.
ジャーナル Sci Rep
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.
巻・号 6
ページ 32428
公開日 2016-8-31
DOI 10.1038/srep32428
PII srep32428
PMID 27577048
PMC PMC5006242
MeSH Complement C5a / genetics Complement C5a / metabolism Gene Expression Regulation, Leukemic* Glutarates / metabolism* Glutarates / pharmacology Humans Interleukin-6 / genetics Interleukin-6 / metabolism Interleukin-8 / genetics Interleukin-8 / metabolism Isocitrate Dehydrogenase / genetics Isocitrate Dehydrogenase / metabolism Junctional Adhesion Molecule B / genetics Junctional Adhesion Molecule B / metabolism Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / metabolism* Leukemia, Myeloid, Acute / pathology Mesenchymal Stem Cells / drug effects* Mesenchymal Stem Cells / metabolism Mesenchymal Stem Cells / pathology Mitogen-Activated Protein Kinase 1 / genetics Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / genetics Mitogen-Activated Protein Kinase 3 / metabolism Mutation Myeloid Cells / drug effects* Myeloid Cells / metabolism Myeloid Cells / pathology NF-kappa B / genetics* NF-kappa B / metabolism NIMA-Interacting Peptidylprolyl Isomerase / genetics NIMA-Interacting Peptidylprolyl Isomerase / metabolism Paracrine Communication / drug effects* Paracrine Communication / genetics Phosphorylation Primary Cell Culture Protein Stability Reactive Oxygen Species / metabolism Receptors, CXCR4 / genetics Receptors, CXCR4 / metabolism Signal Transduction
IF 3.998
リソース情報
ヒト・動物細胞 StromaNKtert(RCB2350)