High serum ferritin is associated with genetic instability in myelodysplastic neoplasms.

PURPOSE: Serum ferritin is an independent prognostic marker in myelodysplastic neoplasms (MDS) and serves as a surrogate parameter for iron overload. Oxidative stress derived from iron overload may induce genomic damage, thereby promoting genetic instability and disease progression in MDS. We aimed to evaluate a possible association between iron overload via serum ferritin and various parameters for genetic instability in MDS.

METHODS

Fifty-one patients with confirmed MDS were analyzed and divided into three groups based on ferritin levels: non-elevated (≤ 275 µg/L), moderately elevated (> 275 and < 1000 µg/L), and highly elevated (≥ 1000 µg/L). Genetic instability was assessed by cytogenetic analysis and somatic mutation profiling. DNA double-strand breaks were quantified by γH2AX-foci in CD34+ peripheral blood cells, and telomere length was measured by flow-FISH.

RESULTS

Elevated serum ferritin was associated with increased cytogenetic abnormalities and somatic mutations at genomic regions commonly involved in MDS, higher levels of double-strand breaks, and shortened telomeres in granulocytes but not in lymphocytes. Markers of early-stage genetic instability, such as double-strand breaks and telomere shortening in granulocytes, were detectable at moderately elevated ferritin > 275 µg/L, whereas markers for advanced-stage genetic aberrations, including somatic mutations and cytogenetic aberrations, were more prominent at ferritin levels ≥ 1000 µg/L.

CONCLUSION

These findings support the hypothesis that iron overload, reflected by elevated ferritin as surrogate parameter, may contribute to and/or increase genetic instability in MDS patients with ineffective hematopoiesis. Notably, correlations were observed at ferritin levels below current thresholds for initiating iron chelation therapy, indicating clinical relevance early in the disease course.