Although iron overload is a common feature in myelodysplastic syndromes (MDSs), it remains unclear how iron excess is detrimental for disease pathophysiology. Taking advantage of complementary approaches, we analyzed the impact of iron overload and restriction achieved through genetic activation of ferroportin (FPN) via the C326S mutation (FPNC326S) and pharmacologic inhibition (vamifeport) of the iron exporter FPN, respectively, in a MDS mouse model. Although FPNC326S-induced iron overload did not significantly improve the late stages of erythroid maturation, vamifeport-mediated iron restriction ameliorated anemia and red blood cell maturation in MDS mice, through the reduction of oxidative stress and apoptosis in erythroid progenitors. Iron overload aggravated, and restriction alleviated, reactive oxygen species formation, DNA damage, and cell death in hematopoietic stem and progenitor cells, resulting in altered cell survival and quality. Finally, myeloid bias, indicated by expanded bone marrow myeloid progenitors and circulating immature myeloid blasts, was exacerbated by iron excess and attenuated by iron restriction. Overall, vamifeport treatment resulted in improved anemia and significant survival increment in MDS mice. Interestingly, the combined therapy with vamifeport and the erythroid maturation agent luspatercept has superior effect in improving anemia and myeloid bias as compared with single treatments and offers additive beneficial effects in MDS. Our results prove, to our knowledge, for the first time in a preclinical model, that iron plays a pathologic role in transfusion-independent MDS. This is likely aggravated by transfusional iron overload, as suggested by observations in the FPNC326SMDS model. Ultimately, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS.

中文翻译：

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临床前研究中遗传性铁超负荷加重，药理学铁限制改善 MDS 病理生理学


尽管铁超负荷是骨髓增生异常综合征 （MDS） 的常见特征，但尚不清楚铁过量如何对疾病病理生理学有害。利用互补方法，我们分析了在 MDS 小鼠模型中，分别通过 C326S 突变 （FPNC326S） 和铁输出因子 FPN 的药理学抑制 （vamifeport） 对铁转运蛋白 （FPN） 的遗传激活实现铁过载和限制的影响。尽管 FPNC326S 诱导的铁过载并未显著改善红细胞成熟的晚期，但 vamifeport 介导的铁限制通过减少红细胞祖细胞的氧化应激和细胞凋亡，改善了 MDS 小鼠的贫血和红细胞成熟。造血干细胞和祖细胞中的铁过载加剧并减轻了限制、活性氧形成、DNA 损伤和细胞死亡，导致细胞存活和质量改变。最后，骨髓偏倚，以扩大的骨髓骨髓祖细胞和循环的未成熟髓系原始细胞为标志，因铁过量而加剧，因铁限制而减弱。总体而言，vamifeport 治疗导致 MDS 小鼠的贫血得到改善和存活率显着增加。有趣的是，与单一治疗相比，vamifeport 和红细胞成熟剂 luspatercept 的联合治疗在改善贫血和髓系偏倚方面具有更好的效果，并在 MDS 中提供附加的有益效果。据我们所知，我们的结果首次在临床前模型中证明，铁在非输血性 MDS 中起病理作用。输血铁超负荷可能加剧了这种情况，如 FPNC326SMDS 模型中的观察结果所示。 最终，药物 FPN 抑制的有益作用揭示了早期预防非输血性 MDS 中铁毒性的治疗潜力。