Here, Lin et al. find loss-of-function mutations in D2-hydroxyglutarate dehydrogenase (D2HGDH), which converts D2-HG to alpha-ketoglutarate (α-KG), in diffuse large B-cell lymphomas and show that D2HGDH via α-KG regulates the expression and activity of IDH2. Here, IDH2 is linked to diffuse large B-cell lymphoma.