Loss of Hfe impairs hematopoietic stem and progenitor cell function

HFE encodes a nonclassical major histocompatibility complex class I molecule involved in iron homeostasis. Among the known HFE variants, p.Cys282Tyr in homozygosity accounts for >90% of cases of hemochromatosis (HFE-HC), a genetic disorder characterized by systemic iron overload. HFE plays a well-established role in systemic iron control through hepatic regulation of hepcidin expression. However, its putative role within the hematopoietic system remains underexplored. Prior studies have demonstrated that Hfe is expressed in erythroid progenitors, influencing iron uptake and erythropoiesis. HFE has also been identified as a negative regulator of CD8⁺ T-cell activation and, in mice, its loss contributes to dysplastic hematopoiesis under oxidative stress conditions. Here, we investigated the role of Hfe/HFE in mouse and human hematopoietic stem and progenitor cell (HSPC) function. We demonstrate that loss of intrinsic hematopoietic Hfe/HFE leads to reduced numbers and function of HSPC, likely through enhanced cellular iron uptake and differentiation. Consistently, patients with HFE-HC had reduced peripheral blood clonogenic activity and changes in peripheral blood counts that may partially reflect ineffective hematopoiesis. Analysis of data from the UK Biobank revealed that women carrying p.Cys282Tyr variant in homozygosity are at increased risk of myelodysplastic syndrome (odds ratio, 3.50; 95% confidence interval, 1.64-7.49). Altogether, our data demonstrate that intrinsic Hfe/HFE affects HSPC function and supports future studies exploring its liver-independent role in hematopoiesis and hematologic malignancies.