Iron homeostasis governs erythroid phenotype in polycythemia vera
- Author(s)
- Bennett, C; Jackson, VE; Pettikiriarachchi, A; Hayman, T; Schaeper, U; Moir-Meyer, G; Fielding, K; Ataide, R; Clucas, D; Baldi, A; Garnham, AL; Li-Wai-Suen, CSN; Loughran, SJ; Baxter, EJ; Green, AR; Alexander, WS; Bahlo, M; Burbury, K; Ng, AP; Pasricha, SR;
- Details
- Publication Year 2023-06-29,Volume 141,Issue #26,Page 3199-3214
- Journal Title
- Blood
- Publication Type
- Research article
- 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 concentrations, placing them at risk of life-threatening thrombotic events. Our genome-wide association study of 440 PV cases and 403 351 controls using UK Biobank data showed that single nucleotide polymorphisms in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed overrepresentation of homozygous HFE variants in patients with PV. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of mouse models of PV, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Furthermore, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130-coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
- Publisher
- American Society of Hematology
- Keywords
- Animals; Mice; *Polycythemia Vera/genetics/complications; Hepcidins/genetics; Genome-Wide Association Study; Iron/metabolism; Phenotype; Homeostasis
- Department(s)
- Clinical Haematology
- PubMed ID
- 36928379
- Publisher's Version
- https://doi.org/10.1182/blood.2022016779
- Open Access at Publisher's Site
https://doi.org/10.1182/blood.2022016779- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-09-12 07:43:56
Last Modified: 2023-09-12 07:44:44