IDH Mutations, 2-Oxoglutarate-dependent Dioxygenases, and Leukemia

Somatic isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations have been discovered in a variety of neoplasms, including glioblastomas and acute myelogenous leukemias. Cancer-associated IDH mutants produce large quantities (low mM) of the R enantiomer of 2-hydroxyglutarate (R-2HG). R-2HG resembles 2-oxoglutarate, which is a Krebs Cycle intermediate and an essential cofactor for a variety of enzymes including the ~70 2-oxoglutarate-dependent dioxygenases. Included among these enzymes are the EglN prolyl hydroxylases that earmark the hypoxia-inducible factor (HIF) for destruction under normoxic conditions, the JmjC histone demethylases, and the ten-eleven translocation (TET) enzymes that hydroxylate methylcytosine residues. In general, both R-2HG and the alternative enantiomer, S-2HG, inhibit 2-oxoglutarate-dependent dioxygenases, with the (S) enantiomer typically being more potent, at least as measured in vitro. We recently discovered that R-2HG, in contrast to S-2HG, potentiates, rather than inhibits, EglN activity; we linked this, and subsequent downregulation of HIF, to the ability of mutant IDH1 to transform human astrocytes. Moreover, we found that R-2HG, but not S-2HG, is sufficient to promote leukemic transformation and that its effects are reversible. In this setting, inactivation of EglN, as occurs with S-HG, appears to be antithetical to transformation. R-2HG promotes leukemic transformation by inhibiting targets such as TET2, while sparing EglN activity. Recent clinical data show that inhibiting R-2HG production can induce complete remissions in some patients with IDH mutant leukemias. We are currently trying to identify the relevant downstream targets of TET2 in IDH mutant leukemias and are also exploring whether loss of EglN activity has antileukemic effects in mouse models in vivo. Finally, we are exploring whether any other 2-oxoglutarate-dependent dioxygenases, such as the RBP2/JARID1A/KDM5A, might be viable drug targets in leukemia.