title: The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells.
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.
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors: Jing-Yi
authors: JY
authors: Chen
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors: You-Syuan
authors: YS
authors: Lai
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.
authors: Hui-Jen
authors: HJ
authors: Tsai
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan.
authors: Cheng-Chin
authors: CC
authors: Kuo
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan.
authors: B Linju
authors: BL
authors: Yen
authors: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
authors: Su-Peng
authors: SP
authors: Yeh
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.|Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
authors: H Sunny
authors: HS
authors: Sun
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.|Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 804, Taiwan.
authors: Wen-Chun
authors: WC
authors: Hung
mesh_terms: D015936:Complement C5a / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D005977:Glutarates / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D062765:Junctional Adhesion Molecule B / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D022423:Myeloid Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects* / Q000235:genetics; D010766:Phosphorylation; D061251:Primary Cell Culture; D055550:Protein Stability; D017382:Reactive Oxygen Species / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C527276:CXCR4 protein, human; D005977:Glutarates; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D062765:Junctional Adhesion Molecule B; D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4; C019417:alpha-hydroxyglutarate; D015936:Complement C5a; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C000606846:PIN1 protein, human