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

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

“…Expression of these mutations in mouse models initiate hematologic malignancy characterized by an increase in early hematopoietic progenitors, splenomegaly, anemia, hypermethylated histones, and altered DNA methylation patterns similar to those found in patients with AML with IDH1/2 mutations. It has been also shown that IDH1 mutant mice develop myeloid dysplasia via disturbance of heme biosynthesis and erythropoiesis, thus highlighting the essential role of IDH1 in normal erythropoiesis ( 116 ). Overexpression of mutant IDH enzymes can induce histone and DNA hypermethylation, as well as block cellular differentiation, which can be reversed by small molecule inhibition of the mutant enzymes ( 117 – 119 ).…”

IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy

“…DNA and histone hypermethylation is a feature that is observed across most investigated types of cancer that frequently contain IDH1/2mt, such as glioma, 40 chondrosarcoma, 41,42 cholangiocarcinoma, 20 and AML. 16 Furthermore, genomic hypermethylation and an associated block of differentiation are induced by the expression of mtIDH1/2 or the administration of D-2-HG in cell models related to these types of cancer, such as primary human astrocytes, 43,44 human and mouse neural stem cells, [45][46][47] human and mouse mesenchymal stem cells, 42,48 mouse hepatoblasts, 49 and mouse hematopoietic cells, 16,50,51 but also human embryonic cells and mouse adipocytes. 52 These findings were associated with an increased number of IDH1/2mt cancerous stem cells when these mutations were induced in benign stem or progenitor cells of these tissues.…”

“…The resulting succinyl-CoA deficiency attenuates heme biosynthesis in IDH1mt hematopoietic cells, blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells. 51…”

“…89 This mechanism is supplementary to the mtIDH1/2-inhibitor-induced restoration of the abovementioned deficiency of succinyl-CoA in IDH1/2mt myeloid progenitor cells, a critical component for heme biosynthesis. 51…”

Myelodysplastic Syndromes and Metabolism

“…This effect is particularly prominent in IDH1 -mutated MDS and AML, where the defective IDH1 enzyme results in a very high accumulation of 2-HG rather than α-KG [ 38 ]. Recently, published data in mice have shown that 2-HG inhibits oxoglutarate dehydrogenase activity and reduces succinyl-CoA production, which leads to attenuation of heme biosynthesis and ineffective erythropoiesis [ 39 ].…”