The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells.

Jing-Yi Chen,Wen-Chun Hung,H Sunny Sun,Hui-Jen Tsai,You-Syuan Lai,Su-Peng Yeh,Cheng-Chin Kuo,B Linju Yen

doi:10.1038/srep32428

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.

Highlights

Isocitrate dehydrogenease 1 (IDH1) and IDH2 mutations were originally identified in acute myeloid leukemia (AML) and glioblastoma multiforme by genome-wide sequencing[1,2]
To the best of our knowledge, this study provides the first evidence showing the effect of R-2HG on bone marrow stromal cells
We demonstrate that AML cell-derived R-2HG may be helpful for the establishment of a tumor-promoting bone marrow stromal niche for AML cells by producing growth-proliferating cytokine (IL-6) and enhancing cell-cell interaction (VLA-4/vascular cell adhesion molecule 1 (VCAM-1)) to increase proliferation and chemoresistance

Summary

Introduction

Isocitrate dehydrogenease 1 (IDH1) and IDH2 mutations were originally identified in acute myeloid leukemia (AML) and glioblastoma multiforme by genome-wide sequencing[1,2] Mutations of these two enzymes have been found in other cancers including chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma[3,4,5]. Infection of primary bone marrow cells with mutant IDH1 accelerates cell cycle transition and promotes leukemogenesis in mice[11]. IDH2 mutants cooperate with oncogenic FLT3 or N-RAS to drive leukemia in mice by impairing the differentiation of cells of myeloid lineage[13]. We demonstrated that R-2HG induced NF-κB activation in bone marrow stromal cells to create a supportive niche for AML cells

Methods

Results

Conclusion