Iron Overload, Heme Oxygenase-1 Expression and Drug Resistance in Acute Leukemia

Abstract

Serum ferritin before transplantation predicts death with unusual reliability, and it is routinely read as a measure of iron overload. The pattern of that mortality, and what direct iron measurement shows, suggest a substantial part of the signal is inflammation rather than iron, which decides whether chelation could help. Objectives: To review the published evidence on iron overload and heme oxygenase-1 expression in acute leukaemia: what raised ferritin predicts, whether it reflects iron burden, how the enzyme contributes to chemoresistance, and where the two lines of evidence meet. Material and Methods: Narrative review of prospective and retrospective transplant cohorts, imaging studies, laboratory work and systematic reviews indexed in PubMed and the major haematology journals. Studies were eligible if they reported the association between iron status or heme oxygenase-1 expression and outcome or drug sensitivity in a defined acute leukaemia or myelodysplastic syndrome population. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators. Results: In a prospective multicentre study of 298 allogeneic transplant recipients using a ferritin threshold of 1,500 micrograms per litre, overall survival (HR 2.5, 95% CI 1.5-4.1, p = 0.0005) and progression-free survival (HR 2.4, 95% CI 1.6-3.8, p < 0.0001) were inferior above the cut-off, with excess mortality from
both higher relapse (HR 2.2) and higher non-relapse mortality (HR 3.1), the latter driven by infection-related death (HR 3.9, 95% CI 1.6-9.7, p = 0.003). Neither the incidence nor the severity of graft-versus-host disease was associated with ferritin. In a prospective imaging study, ferritin correlated with estimated liver iron concentration at r = 0.75, largely dependent on transfusion history, while labile plasma iron elevation was rare and hepcidin was appropriately raised. In laboratory work, a cytarabine and daunorubicin-resistant cell line showed high heme oxygenase-1 expression, and silencing the gene restored chemosensitivity with reduced hypoxia-inducible factor 1-alpha and glucose transporter 1, increased caspase-3 and caspase-8 and decreased BCL-2. Conclusion: Ferritin is a robust prognostic marker and a poor measure of iron, and the mortality it predicts is infectious rather than the organ toxicity iron
overload would cause. Heme oxygenase-1 sits at the junction of the two, being both an iron-releasing enzyme and a stress-response gene conferring resistance. Abbreviations: AML – Acute Myeloid Leukaemia, ALL – Acute Lymphoblastic Leukaemia, MDS – Myelodysplastic Syndrome, HO-1 – Heme Oxygenase-1, NRF2 – Nuclear Factor Erythroid 2-Related Factor 2, HIF-1α – Hypoxia-Inducible Factor 1-Alpha, GLUT1 – Glucose Transporter 1, LIC – Liver Iron Concentration, LPI – Labile Plasma Iron, SF – Serum Ferritin, NRM – Non-Relapse Mortality, GVHD – Graft-Versus-Host Disease, alloSCT – Allogeneic Stem Cell Transplantation, ROS – Reactive Oxygen Species.