Iron homeostasis governs erythroid phenotype in Polycythemia Vera

Bennett, C; Jackson, VE; Pettikiriarachchi, A; Hayman, T; Schaeper, U; Moir-Meyer, GL; Fielding, KL; Ataide, R; Clucas, D; Baldi, AJ; Garnham, AL; Li-Wai-Suen, CS; Loughran, SJ; Baxter, EJ; Green, AR; Alexander, WS; Bahlo, M; Burbury, K; Ng, AP; Pasricha, SR

Author(s): Bennett, C; Jackson, VE; Pettikiriarachchi, A; Hayman, T; Schaeper, U; Moir-Meyer, GL; Fielding, KL; Ataide, R; Clucas, D; Baldi, AJ; Garnham, AL; Li-Wai-Suen, CS; Loughran, SJ; Baxter, EJ; Green, AR; Alexander, WS; Bahlo, M; Burbury, K; Ng, AP; Pasricha, SR;
Details: Publication Year 2023-03-16,Volume 141,Issue #26,Page 3199-3214
Journal Title: Blood
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 utilizing 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 variants in PV patients. HFE influences the 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 signaling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
Keywords: Animals; Mice; *Polycythemia Vera/genetics/complications; Hepcidins/genetics; Genome-Wide Association Study; Iron/metabolism; Phenotype; Homeostasis
Research Division(s): Bioinformatics; Blood Cells And Blood Cancer; Population Health And Immunity; Bioinformatics; Blood Cells and Blood Cancer
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: 2023-03-29 08:33:58

Last Modified: 2023-07-12 08:28:28