Genetic iron overload exacerbates and pharmacological iron restriction improves mds pathophysiology in preclinical studies

Although iron overload is a common feature in myelodysplastic syndromes (MDS), it remains unclear whether and how iron excess is detrimental for MDS 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 (FPN) in NUP98-HOXD13 MDS mice, respectively. At steady-state MDS mice show ineffective erythropoiesis, anemia and low blood WBC count associated with an iron overload phenotype, hallmarked by low hepcidin, elevated transferrin saturation, non-transferrin-bound iron and tissue iron deposition. This phenotype is aggravated in iron-loaded FPNC326S MDS mice and alleviated in iron-restricted MDS mice receiving vamifeport. While iron excess caused by FPNC326S did not significantly improve erythropoiesis and hematologic parameters, iron restriction significantly ameliorated anemia and RBC maturation in MDS mice, by reducing oxidative stress and apoptosis in erythroid progenitors. Surprisingly, myeloid bias, together with bone marrow inflammation, was exacerbated by FPNC326S-induced iron overload and attenuated by vamifeport-mediated iron restriction, suggesting a role for iron in myeloid expansion. Finally, iron overload aggravated and restriction alleviated ROS formation, DNA damage and pyroptotic cell death in HSPCs, resulting in altered HSPC quality/survival. Through these effects, vamifeport resulted in improved anemia and a significant survival increment in MDS mice. Our results show for the first time in preclinical models that iron plays a pathologic role in transfusion-independent MDS, likely aggravated by transfusion. Finally, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS. Although iron overload is a common feature in myelodysplastic syndromes (MDS), it remains unclear whether and how iron excess is detrimental for MDS 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 (FPN) in NUP98-HOXD13 MDS mice, respectively. At steady-state MDS mice show ineffective erythropoiesis, anemia and low blood WBC count associated with an iron overload phenotype, hallmarked by low hepcidin, elevated transferrin saturation, non-transferrin-bound iron and tissue iron deposition. This phenotype is aggravated in iron-loaded FPNC326S MDS mice and alleviated in iron-restricted MDS mice receiving vamifeport. While iron excess caused by FPNC326S did not significantly improve erythropoiesis and hematologic parameters, iron restriction significantly ameliorated anemia and RBC maturation in MDS mice, by reducing oxidative stress and apoptosis in erythroid progenitors. Surprisingly, myeloid bias, together with bone marrow inflammation, was exacerbated by FPNC326S-induced iron overload and attenuated by vamifeport-mediated iron restriction, suggesting a role for iron in myeloid expansion. Finally, iron overload aggravated and restriction alleviated ROS formation, DNA damage and pyroptotic cell death in HSPCs, resulting in altered HSPC quality/survival. Through these effects, vamifeport resulted in improved anemia and a significant survival increment in MDS mice. Our results show for the first time in preclinical models that iron plays a pathologic role in transfusion-independent MDS, likely aggravated by transfusion. Finally, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS.