IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis
IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis
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IDH1突变通过干扰血红素生物合成和红细胞生成导致小鼠骨髓发育不良
DOI：
10.1182/blood.2020007075
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发表时间：
2021-02-18
期刊：
影响因子：
20.3
通讯作者：
Ye, Jing
中科院分区：
文献类型：
--
作者：
Gu, Yu;Yang, Risheng;Ye, Jing
异柠檬酸脱氢酶（IDH）突变是骨髓疾病中常见的遗传改变，包括急性髓性白血病（AML）和骨髓增生异常综合征（MDS）。表观遗传变化，包括异常组蛋白和DNA甲基化，与造血祖细胞的致病性积累有关，但IDH突变本身是否以及如何影响造血仍不清楚。在这里，我们发现IDH 1突变小鼠发生骨髓发育不良，这些动物表现出贫血，无效的红细胞生成，并增加未成熟的祖细胞和成红细胞。在这些小鼠的红系细胞中，D-2-羟基戊二酸（由突变IDH 1酶产生的异常代谢物）抑制酮戊二酸脱氢酶活性并减少琥珀酰辅酶A（CoA）的产生。这种琥珀酰辅酶A缺乏减弱了IDH 1突变型造血细胞中的血红素生物合成，从而阻断了成红细胞晚期的红系分化和造血干细胞的红系定型，而外源性琥珀酰辅酶A或5-ALA挽救了IDH 1突变型红系细胞中的红系生成。血红素缺乏也会损害血红素氧合酶-1的表达，从而降低重要的血红素催化剂如胆绿素和胆红素的水平。这些缺陷导致过量活性氧物质的积累，其诱导IDH 1突变型红系细胞的细胞死亡。我们的研究结果清楚地显示了IDH 1在正常红细胞生成中的重要作用，并描述了其突变如何导致骨髓疾病。因此，这些数据对设计IDH突变型肿瘤的新治疗方法具有重要意义。
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, and increased immature progenitors and erythroblasts. In erythroid cells of these mice, D-2-hydroxyglutarate, an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase activity and diminishes succinyl-coenzyme A (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, while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species that induce the cell death of IDH1-mutant erythroid cells. Our results clearly show the essential role of IDH1 in normal erythropoiesis and describe how its mutation leads to myeloid disorders. These data thus have important implications for the devising of new treatments for IDH-mutant tumors.