Iron homeostasis governs erythroid phenotype in Polycythemia Vera

Abstract

Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients’ hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilising UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE mutations in PV patients. HFE influences expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signalling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

Hepcidin mimetics in polycythemia vera: resolving the irony of iron deficiency and erythrocytosis

“…1) [45][46][47]. A recent report suggests that ERFE may have a diminished role relative to that of inflammation in regulating hepcidin expression in polycythemia vera patients [48]. In this study, deletion of Erfe in polycythemia vera mice did not alter hepcidin levels or disease severity, resulting in unchanged Hct levels or RBC numbers.…”

“…The authors further explored the hypothesis that inflammation associated with polycythemia vera leads to hepcidin upregulation. Using a human hepatocyte cell line, HepG2 cells, the authors demonstrated that the increased hepcidin expression was induced by polycythemia vera plasma but not plasma from normal controls and was normalized by blocking IL-6 binding to its receptor [48]. These findings suggest that inflammatory cytokines in polycythemia vera may be crucial to disordered iron utilization.…”

Novel Therapeutic Approaches in Thalassemias, Sickle Cell Disease and Other Red Cell Disorders

“…36,41,42 These agents could be successful in disorders of erythropoiesis with preserved maturation profile such as polycythemia vera (PV). [43][44][45][46] Finally, the modulation of iron homeostasis as therapeutic option has been also explored in patients with SCD. [47][48][49][50][51] In SCD, iron restriction decreases HbS synthesis, resulting in reduction of the cellular HbS concentration, which in turn modulates the kinetic of HbS polymerization with a secondary beneficial impact on red cell oxidative stress (Figure 1).…”

Serum iron variation is circadian-regulated and linked to the harmonic circadian oscillations of erythropoiesis and hepaticTfrcexpression in mice

“…RT-qPCR from liver, spleen and bone marrow samples was performed as previously described. 27 Data is presented as -ΔΔCt or -ΔCt, where ΔCt = Ct target gene -Ct Hprt1 and ΔΔCt = ΔCt sample -mean ΔCt control (ZT0; ZT4 dark fed; CT0 or Bmal1+/+ ZT4) . Primers used for RT-qPCR are in the table below:…”

“…Serum iron and liver and spleen non-heme iron was measured as previously described. 27 Serum sTfR and hepcidin were measured by ELISA (Abcam and Intrinsic Life Sciences, respectively).…”