Blood:IDH1突变通过干扰血红素合成和红细胞生成导致髓系发育不良

2020-12-04 MedSci原创 MedSci原创

异柠檬酸脱氢酶(IDH)突变是包括急性髓系白血病(AML)和骨髓增生异常综合征(MDS)在内的髓系疾病中常见的基因变异。表观遗传学变异,包括组蛋白和DNA甲基化异常,与造血祖细胞的病理性聚集有关,但I

异柠檬酸脱氢酶(IDH)突变是包括急性髓系白血病(AML)和骨髓增生异常综合征(MDS)在内的髓系疾病中常见的基因变异。表观遗传学变异,包括组蛋白和DNA甲基化异常,与造血祖细胞的病理性聚集有关,但IDH突变本身是否以及如何影响造血仍不清楚。

在该研究中,研究人员发现IDH1基因突变的小鼠会出现髓系发育不良,表现为贫血、无效的红细胞生成、幼稚祖细胞和红细胞增多。

在这些小鼠的红系细胞中,由突变型IDH1酶产生的异常代谢物D-2-羟基戊二酸(D-2HG)抑制了氧戊二酸脱氢酶(OGDH)的活性,进而减少了琥珀酰辅酶A的产生。

这种琥珀酰辅酶A缺乏抑制了IDH1突变的造血细胞中血红素的生物合成,从而在成红细胞末期阻断红系分化和造血干细胞(HSC)的红系定型,而外源性的琥珀酰辅酶A或5-ALA可挽救IDH1突变型红系细胞的红细胞生成。

血红素缺乏还会影响血红素加氧酶-1(HO-1)的表达,从而降低重要的血红素分解代谢产物如胆绿素和胆红素的水平。这些缺陷还会使活性氧(ROS)过度积累,导致IDH1突变型红系细胞死亡。

综上,该研究结果清楚地证明了IDH1在正常红细胞生成中具有重要作用,并阐述了其突变是如何导致髓系疾病的。该研究对开发IDH突变型肿瘤的新治疗方法具有重要意义。

原始出处:

Gu Yu,Yang Risheng,Yang Ying et al. IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis.Blood, 2020.

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    2020-12-06 neurowu
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    2020-12-04 ms3000001340106445

    特别详细,受益匪浅

    0

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