Cancer-related anemia is present in more than 60% of newly diagnosed cancer patients and is associated with substantial morbidity and high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates and improve quality of life. Clinical studies have observed an unexpected improvement in hemoglobin and RBC transfusion-independence in patients with acute myeloid leukemia (AML) treated with the isocitrate dehydrogenase 2 (IDH2) mutant-specific inhibitor enasidenib, leading to improved quality of life without a reduction in AML disease burden. Here, we demonstrate that enasidenib enhanced human erythroid differentiation of hematopoietic progenitors. The phenomenon was not observed with other IDH1/2 inhibitors and occurred in IDH2-deficient CRISPR-engineered progenitors independently of D-2-hydroxyglutarate. The effect of enasidenib on hematopoietic progenitors was mediated by protoporphyrin accumulation, driving heme production and erythroid differentiation in committed CD71⁺ progenitors rather than hematopoietic stem cells. Our results position enasidenib as a promising therapeutic agent for improvement of anemia and provide the basis for a clinical trial using enasidenib to decrease transfusion dependence in a wide array of clinical contexts.

中文翻译：

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Enasidenib 独立于异柠檬酸脱氢酶 2 驱动人类红系分化。

超过 60% 的新诊断癌症患者存在癌症相关性贫血，并且与高发病率和高医疗费用相关。迫切需要增强红细胞生成的药物来降低输血率和提高生活质量。临床研究观察到用异柠檬酸脱氢酶 2 (IDH2) 突变特异性抑制剂 enasidenib 治疗的急性髓性白血病 (AML) 患者的血红蛋白和 RBC 输血依赖性出现意外改善，从而改善生活质量而不减少 AML 疾病负担。在这里，我们证明 enasidenib 增强了造血祖细胞的人类红系分化。该现象在其他 IDH1/2 抑制剂中未观察到，并且独立于 D-2-羟基戊二酸发生在 IDH2 缺陷型 CRISPR 工程祖细胞中。⁺祖细胞而不是造血干细胞。我们的研究结果将 enasidenib 定位为改善贫血的有前景的治疗药物，并为使用 enasidenib 在广泛的临床环境中降低输血依赖的临床试验提供基础。