TET DNA hydroxylases are alpha-ketoglutarate (αKG)-dependent enzymes that catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), thus promoting DNA demethylation. Mapping of 5hmC marks at single base resolution demonstrated that the main role of TET enzymes is to maintain gene enhancers hypomethylated and active. Enhancers are genomic areas to which transcription factors bind to modulate gene expression programs. Hyperactive clusters of enhancers that are densely occupied by transcriptional factors are termed super- enhancers and are typically found in cancer. Like promoters, enhancers/super-enhancers are regulated by their DNA methylation status, a process that often goes awry in cancer. Thus, given that active enhancers and super- enhancers are oncogenic in nature, and that TET enzymes maintain them hypomethylated and active, we postulate that increased TET activity may itself be oncogenic. Mitochondria function as signaling organelles by generating substrates that fuel epigenetic changes, including for example acetylation and methylation of DNA and histones, respectively. Recently, we and others described a subtler interplay between mitochondria and epigenetics, wherein the levels of the intermediate metabolites αKG and 2-hydroxyglutarate were found to modulate the activity of TET enzymes, thus controlling DNA methylation. These findings led us to hypothesize that intermediary metabolism plays as an important role in the control of DNA methylation. Specifically, we posited that the mitochondrial enzymes D-2- and L-2-hydroxyglutarate dehydrogenase (D2HGDH and L2HGDH), which catalyze the interconversion of 2-HG to αKG, are integral to the cross talk between mitochondrial metabolism, TET function and super-enhancer demethylation/activation. To expand on this initial concept, we sought to identify upstream signals that regulate D2HGDH and L2HGDH expression and, consequently, influence TET function and enhancer methylation/activity. Using reporter and ChIP assays, inducible cell lines and mouse models, we recently reported that MYC transcriptionally activates D2HGDH and L2HGDH and, in a D2HGDH/L2HGDH/αKG-dependent manner, induces TET function leading to DNA demethylation in vitro and in vivo. Remarkably, we discovered that the MYC/D2-L2HGDH/αKG axis also promotes the nuclear accumulation of TET1, TET2 and TET3, in association with enhanced O-GlcNAcylation, a post-translational modification executed by another mitochondrial enzyme, O-GlcNAc transferase (OGT). Further, we preliminarily showed that in in diffuse large B cell lymphoma (DLBCL), MYC levels associated with enhancer methylation and target gene expression. Together, these data uncovered a novel mitochondrial signaling axis which includes MYC at the proximal point, D2/L2HGDH and OGT at the center, and, distally, TET activity and subcellular location. In this proposal, we will use human B cell lymphoma models in vitro and in vivo, to test the overarching hypothesis that intermediary...