P08.65 The mechanisms of oncometabolites in epigenetic control, DNA repair, neural development and gliomagenesis

Eight genes encoding for subunits of four distinct metabolic enzymes (IDH1, IDH2, SDH and FH) are mutated in various types of human malignancies. Of these 8 genes, IDH1 is the most frequently mutated, in particular in low-grade gliomas. Oncogenic mutation in IDH1 and IDH2 abolish their normal catalytic activity in producing α-ketoglutarate (αKG) and also gain a new function to produce oncometabolite D-2-hydroxyglutarate (D2HG). We previously discovered that D2HG, and its enantiomer, L2HG, act a competitive inhibitor of αKG and inhibit both αKG- dependent JmiC family of histone demethylases and TET family of DNA demethylases. These discoveries provide a molecular basis for the CpG island methylator phenotype (CIMP) observed in IDH-mutant gliomas. More recently, we demonstrated that D2HG also inhibits αKG- dependent alkB homolog (ALKBH) family of DNA repair enzymes, sensitizing IDH1-mutant glioma cells to alkylating agents such as methyl methanesulfonate (MMS), N-methyl-N0- nitro-N-nitrosoguanidine (MNNG) and CCNU/lomustine. These results provide a molecular basis for the clinical benefits seen in IDH-mutant glioma patients who in addition to radiation therapy (RT) received a chemotherapy of procarbazine, CCNU/lomustine, and vincristine (PCV). These results also suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents may merit exploration for treating IDH-mutated cancer patients. Accumulation of D2HG and L2HG are also found in rare neurometabolic disorders and brain tumors, known as 2-hydroxyglutaric aciduria. They are caused by mutations targeting genes encoding for either D2HG or L2HG dehydrogenase (D2HGDH and L2HGDH), respectively, that clean up both enantiomers of 2HG. To determine the biochemical and pathophysiological consequences of L2HG accumulation, we created L2hgdh knockout (KO) mice. L2hgdh null mice exhibited a robust increase of L2HG in multiple tissues. The highest L2HG is observed in brain and testis with corresponding increase of histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. These observations provide in vivo evidence to support that L2hgdh mutation leads to L2HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thus offering new insights into the pathophysiology of L2HGA and