國家衛生研究院 NHRI:Item 3990099045/10018
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    題名: The oncometabolite R-2-hydroxyglutarate activates NF-kappa B-dependent tumor-promoting stromal niche for acute myeloid leukemia cells
    其他題名: The oncometabolite R-2-hydroxyglutarate activates NF-κ B-dependent tumor-promoting stromal niche for acute myeloid leukemia cells
    作者: Chen, JY;Lai, YS;Tsai, HJ;Kuo, CC;Yen, BLJ;Yeh, SP;Sun, HS;Hung, WC
    貢獻者: National Institute of Cancer Research;Institute of Cellular and Systems Medicine
    摘要: 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 I kappa B kinase-independent activation of NF-kappa B in bone marrow stromal cells. R-2HG acts via a reactive oxygen species/extracellular signal-regulated kinase (ERK)-dependent pathway to phosphorylate NF-kappa B on the Thr254 residue. This phosphorylation enhances the interaction of NF-kappa B and the peptidyl-prolyl cis-trans isomerase PIN1 and increases the protein stability and transcriptional activity of NF-kappa B. As a consequence, R-2HG enhances NF-kappa B-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.
    日期: 2016-08-31
    關聯: Scientific Reports. 2016 Aug 31;6:Article number 32428.
    Link to: http://dx.doi.org/10.1038/srep32428
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2045-2322&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000382243500003
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84985034390
    顯示於類別:[洪文俊] 期刊論文
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    [顏伶汝] 期刊論文
    [郭呈欽] 期刊論文

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