The Role of L-2-Hydroxyglutarate (L-2-HG) in Normal and Malignant Hematopoiesis
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The metabolite 2-hydroxyglutarate (2HG) can be produced in mirror-image D(R)- or L(S)- enantiomers. Whereas tumors with somatic mutations in isocitrate dehydrogenase (IDH) enzymes produce high levels of D-2HG, virtually all normal and malignant cells selectively produce L-2HG in hypoxic or acidic conditions via promiscuous enzymatic activity of lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) enzymes. Analogous to D-2HG in IDH-mutant cancers, L-2HG can inhibit alpha-ketoglutarate- (αKG-) dependent enzymes, resulting in stabilization of hypoxia-inducible factor (HIF) and accumulation of repressive methyl marks on histones and DNA. Notably, L-2HG has been proposed to function as an oncometabolite in several cancers, including kidney, pancreas, and colon. However, the physiologic functions of endogenous L-2HG remain poorly understood. As normal and malignant blood stem cells reside in hypoxic niches that regulate their function, we hypothesized that hematopoiesis might offer a robust model for investigating the physiologic functions of L-2HG. Using in vitro models of hematopoietic stem/progenitor cell (HSPC) differentiation, we found that L-2HG could enhance repressive chromatin methylation, slow oxidative metabolism, and inhibit differentiation of HSPCs into mature blood lineages. To interrogate the role of endogenous L-2HG in vivo, we developed genetically engineered mouse models that enable tissue-specific manipulation of L-2HG levels via deletion or overexpression of the L-2HG disposal enzyme L2hgdh. In contrast to the effects of L-2HG in vitro, we found that disrupting L-2HG metabolism had no substantial impact on hematopoiesis in mice under basal homeostatic conditions. Surprisingly, however, we found that in contrast to its proposed role as an oncometabolite, depletion of L-2HG enhanced leukemia growth, suggesting that L-2HG functions as a tumor suppressor in leukemia. Our findings indicate that disrupting L-2HG metabolism might be a strategy to target leukemia growth while sparing normal hematopoiesis.