neomorphic mutation confers sensitivity to vitamin B12 via increased dependency on one-carbon metabolism in .

The isocitrate dehydrogenase neomorphic mutation ( ) generates increased levels of cellular D-2-hydroxyglutarate (D-2HG), a proposed oncometabolite. However, the physiological effects of increased D-2HG and whether additional metabolic changes occur in the presence of an mutation are not well understood. We created a model to study the effects of the mutation in a whole animal. Comparing the phenotypes exhibited by the to (D-2HG dehydrogenase) mutant animals, which also accumulate D-2HG, we identified a specific vitamin B12 diet-dependent vulnerability in mutant animals that leads to increased embryonic lethality. Through a genetic screen we found that impairment of the glycine cleavage system, which generates one-carbon donor units, exacerbates this phenotype. Additionally, supplementation with an alternate source of one-carbon donors suppresses the lethal phenotype. Our results indicate that the mutation imposes a heightened dependency on the one-carbon pool and provides a further understanding how this oncogenic mutation rewires cellular metabolism.