The goal of my laboratory is to identify vulnerabilities in leukemia cells that can be targeted therapeutically in the hopes of developing novel strategies to treat hematologic malignancies and other cancers. One of the pathways we study is the hypoxia signaling pathway. EglNs (also called PHD) are oxygen-sensitive 2-oxoglutarate-dependent dioxygenases that catalyze the prolyl hydroxylation of the HIFÎ± (hypoxia-inducible factor) subunit of the HIF heterodimer. This targets HIFÎ± for polyubiquitylation and subsequent proteasomal degradation. Inhibition of EglN results in accumulation of HIFÎ± and subsequent activation of hypoxia-inducible gene transcription. We have found that inhibition of EglN inhibits the proliferation of myeloid leukemia cells, suggesting that HIF functions as a myeloid tumor suppressor. This finding has motivated our efforts to determine if inhibitors of the HIF prolyl hydroxylases, which are now in clinical trials for the treatment of anemia, can have therapeutic benefit in myeloid leukemia. Another focus of my laboratory is studying the mechanisms by which Isocitrate Dehydrogenase (IDH) mutants promote cellular transformation. Wild-type IDH enzymes are metabolic enzymes that convert isocitrate to 2-oxoglutarate. Cancer-associated IDH mutants instead produce R-2-hydroxyglutarate (R-2HG), a metabolite that is normally found at very low levels in cells. R-2HG is necessary and sufficient to mediate the transforming effects of mutant IDH. We are currently working to identify the downstream targets of R-2HG that mediate transformation, and working to identify metabolic vulnerabilities that are induce by the presence of this abnormal metabolite in cells.