# Iron Overload, Clonal Hematopoiesis, and Cancer Risk in Aging and Transfusion-Dependent Populations: A Literature Review

## TL;DR

This paper reviews how iron overload and clonal hematopoiesis in aging and transfusion-dependent populations increase cancer risk and explores potential therapies.

## Contribution

The paper synthesizes current literature to examine the combined impact of iron overload, clonal hematopoiesis, and aging on cancer initiation.

## Key findings

- Iron overload and clonal hematopoiesis increase cancer risk through oxidative stress and DNA damage.
- Iron chelation therapy can reduce iron burden but has compliance and side effect challenges.
- Combining iron chelation with CHIP screening and imaging may prevent malignancy in high-risk patients.

## Abstract

Aging also contributes to cancer risk factor potentiation by disturbed iron metabolism and genomic instability, both of which contribute to enhanced risk of cancer, particularly in transfusion-dependent groups such as patients with β-thalassemia or myelodysplastic syndromes. Systemic iron overload results from chronic transfusions and progressively disturbed iron homeostasis and clonal hematopoiesis of indeterminate potential (CHIP) that contribute to oncogenic burden. All these create a permissive profile in which carcinogenesis is favored by oxidative stress, mitochondrial dysfunctions, immune suppression, and disrupted DNA repair.

This review synthesizes current literature regarding iron overload, clonal hematopoiesis, and aging to examine the combined impact on initiation of cancer (Appendices). It evaluates processes, such as Fenton chemistry, reactive oxygen species (ROS)-mediated DNA damage, pro-inflammatory signals, and hematopoietic clonal expansion, and therapeutic options, such as iron chelation, risk monitoring, and age-targeted therapies in risk-carrying elderly groups.

Iron overload in aging and transfusional individuals is characterized by high ferritin, augmented non-transferrin-bound iron, and oxidative DNA damage, which all raise the risk of cancer, especially hepatocellular carcinoma. Concurrently, clonal hematopoiesis of indeterminate potential (CHIP) increases with age and predisposes individuals to hematologic malignancies and cardiovascular disease. The interaction of these factors increases mutagenesis and inflammation. Iron chelation therapy (ICT) has been found to be effective in the reduction of iron burden and prevention of complications, but side effects and compliance are problematic. Some new evidence suggests that individualized ICT, combined with CHIP screening and non-invasive imaging (e.g., T2* MRI), can prevent malignancy in high-risk patients.

Iron overload in aging and transfusion-dependent populations is a critical, modifiable risk factor for cancer. The accumulation of effects of clonal hematopoiesis underscores the need to incorporate monitoring and intervention strategies. Future research has to define molecular targets in iron and hematopoietic networks to employ individualized therapies that reduce the emergence of cancer and increase health span in aging, vulnerable populations.