1. Genetic iron overload aggravates and pharmacological iron restriction improves MDS pathophysiology in a preclinical study.
- Author
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Antypiuk A, Vance S, Sharma R, Passos ST, Asperti M, Navaneethabalakrishnan S, Durrenberger F, Manolova V, and Vinchi F Prof
- Abstract
Although iron overload is a common feature in myelodysplastic syndromes (MDS), 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 (FPNC326S) and pharmacologic inhibition (vamifeport) of the iron exporter ferroportin in a MDS mouse model, respectively. While 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 ROS 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 to single treatments, and offers additive beneficial effects in MDS. Our results prove 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., (Copyright © 2024 American Society of Hematology.)
- Published
- 2024
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