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

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.