<i>IDH1</i> mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis

Abstract Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, abnormal histone DNA methylation, have been implicated the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether how IDH themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop dysplasia these animals exhibit anemia, ineffective erythropoiesis, increased immature progenitors erythroblasts. In erythroid cells mice, D-2-hydroxyglutarate, an aberrant metabolite produced by mutant IDH1 enzyme, inhibits oxoglutarate activity diminishes succinyl–coenzyme A (CoA) production. This succinyl-CoA deficiency attenuates heme biosynthesis cells, thus blocking differentiation at late erythroblast stage commitment stem while exogenous or 5-ALA rescues erythropoiesis cells. Heme also impairs oxygenase-1 expression, which reduces levels important catabolites such as biliverdin bilirubin. These deficits result accumulation excessive reactive oxygen species induce cell death Our results clearly essential role normal describe its mutation leads to disorders. data implications for devising new treatments IDH-mutant tumors.