Written by: Rhonda Thygesen, CBR Alumni

Edited by: Loulou Cai, PhD Candidate, Cote Lab

Iron is essential for life, but in excess, it can become toxic – especially for patients with Myelodysplastic Syndromes (MDS). MDS are a group of bone marrow disorders that impair normal blood cell production, leading to anemia, increased infection risk, and, in some cases, progression to acute myeloid leukemia. While MDS has various causes, genetic and environmental factors are known to play key roles.

In a recent Blood commentary¹, Dr. Heather Leitch from the CBR highlights groundbreaking research from Antypiuk et al² that links iron overload with the worsening of MDS symptoms, including bone marrow failure and increased risk of leukemia. The study also identifies iron restriction as a promising therapeutic approach².

Figure 1: Effects of IOL in a murine model of MDS.

Iron is a critical component of oxygen transport and metabolism, but too much iron can drive oxidative stress, damaging hematopoietic stem cells and accelerating disease progression³. Iron overload is often caused by genetic mutations, such as those affecting ferroportin, or by excessive iron accumulation from repeated transfusions. In MDS, iron overload worsens anemia and contributes to bone marrow dysfunction⁴. By targeting iron overload, researchers hope to slow disease progression and improve quality of life for MDS patients.

A major breakthrough in this study was the use of the experimental drug vamifeport, which blocks iron uptake and release. In preclinical models, vamifeprot improved red blood cell production and survival rates. When combined with luspatercept, a drug that enhances red cell blood maturation, the results were even more promising. These findings suggest that iron restriction could become a cornerstone of MDS management².

The root of iron’s toxicity lies in the production of reactive oxygen species (ROS), which cause oxidative damage to DNA, proteins, and lipids³. Reducing iron levels also reduces ROS production, thus protecting the bone marrow environment and potentially slowing MDS progression. This insight could also inform treatments for other blood disorders driven by iron overload.

Interestingly, not all MDS patients are equally impacted by iron overload. Certain forms of MDS, such as those characterized by ring sideroblasts or mutations in the SF3B1 gene, are associated with increased iron accumulation even in the absence of frequent transfusions. For these patients, iron restriction therapies like vamifeport could be especially effective². Clinical trials targeting these specific patient groups may help clarify the role of iron management in MDS treatment.

Iron overload has long been recognized as a major problem in disorders such as thalassemia, where iron chelation therapy has significantly improved outcomes. However, in MDS the connection between iron overload and disease progression has been less clear. This study offers compelling evidence that managing iron levels could be a key component of MDS care. Future research could explore which MDS subtyes are most affected by iron overload and how iron-targeted treatments could complement existing therapies.

The findings by Antypiuk et al. and discussed by Dr. Leitch mark a pivotal moment in understanding the role of iron in MDS. By demonstrating both the harm caused by iron overload and the benefits of iron restriction, this research paves the way for new therapeutic approaches. With clinical trials already underway, the integration of iron management as part of MDS therapy could soon become a reality.

For now, the takeaway is clear: while essential, iron can also drive MDS progression. Managing iron levels offers a promising path towards slowing disease progression and improving outcomes for patients.

References

1. Leitch, H. A. (2025). Iron accelerates MDS progression. Blood, 145(2), 143-144.

1. Antypiuk, A., Vance, S. Z., Sharma, R., Passos, S., Asperti, M., Navaneethabalakrishan, S., … & Vinchi, F. (2025). Genetic iron overload aggravates, and pharmacological iron restriction improves, MDS pathophysiology in a preclinical study. Blood, 145(2), 155-169.
2. Kim, C. H., & Leitch, H. A. (2021). Iron overload-induced oxidative stress in myelodysplastic syndromes and its cellular sequelae. Critical Reviews in Oncology/Hematology, 163, 103367.
3. Santini, V., Girelli, D., Sanna, A., Martinelli, N., Duca, L., Campostrini, N., … & Cappellini, M. D. (2011). Hepcidin levels and their determinants in different types of myelodysplastic syndromes. PloS one, 6(8), e23109.